Joint Annual Research Report 2005 - The Royal Marsden

Annual Research Report 

2005 

The Royal Marsden 

NHS Foundation Trust

INTERNET RESOURCES 


NHS Foundation Trust and 

The Institute of Cancer 

Research together form 

the largest Comprehensive 

Cancer Centre in Europe. 

Our Mission is 

to relieve human suffering 

by pursuing excellence in 

the fight against cancer. 

This will be achieved through: 

• Research and development 

• Education and training of medical, healthcare 

and scientific staff 

• Provision of patient care and treatment of 

the highest quality 

• Attraction and development of resources to their 

optimum effect 

2

ANNUAL RESEARCH REPORT 2005 

CONTENTS 

Review of 2005 - from the Chairmen and Chief Executives 4-11 

Facts and Figures 2005 12 

Academic Dean’s Report 2005 13-16 

Technology Transfer Report 2005 17-19 

RESEARCH THEME 

REVIEW ARTICLES 

CANCER GENETICS 

– CHILDHOOD CANCERS 

Cancer in children 20-25 

Professor Andy Pearson 

CANCER BIOLOGY 

– TARGETED TREATMENTS 

Targeting cancer’s Achilles’ heel 26-29 

Professor Alan Ashworth 

CANCER THERAPEUTICS 

– BREAST CANCER 

Targeted therapies for breast cancer 30-33 

Professors Mitch Dowsett and Ian Smith 

IMAGING RESEARCH & CANCER 

DIAGNOSIS – MAGNETIC RESONANCE 

Magnetic resonance and cancer 34-39 

Professor Martin Leach and Dr Nandita deSouza 


– STRUCTURAL BIOLOGY 

Structure-based drug development 40-43 

Professor Laurence Pearl 


– HAEMATO-ONCOLOGY 

Sleuthing the causes of childhood leukaemia 44-47 

Professor Mel Greaves 

CANCER THERAPEUTICS/CANCER 

BIOLOGY – SKIN CANCER 

Advances in melanoma treatment 48-50 

Professor Martin Gore and Dr Richard Marais 

RADIOTHERAPY – PROSTATE CANCER 

Active surveillance approach to prostate cancer 51-53 

Dr Chris Parker 

HEALTH RESEARCH – CANCER CARE 

The sepsis syndrome 54-57 

Shelley Dolan 

RADIOTHERAPY 

– TAILORED TREATMENT 

Dosimetry for targeted radionuclide therapy 58-61 

Dr Glenn Flux 

Internet Resources 62-63 

Our Research Centres, Departments, Sections and Units 64-65 

Senior Staff and Committees 2005 66-71 

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REVIEW OF 2005 


from the Chairmen and Chief Executives 

Lord Ryder 

Chairman 

The Institute of 

Cancer Research 

Peter Rigby 

Chief Executive 

The Institute of 


Tessa Green 

Chairman 

The Royal 

Marsden NHS 

Foundation Trust 

Cally Palmer 

Chief Executive 

The Royal 

Marsden NHS 


We are delighted to present our 

Annual Research Report for 2005, 

which records another year of 

important achievements and 

significant progress in cancer research. 

It contains in-depth reviews of recent, 

exciting developments in several areas 

of our work, and provides addresses 

for various web resources which give 

comprehensive information on all 

aspects of our activities. 

The Institute of Cancer Research and 

The Royal Marsden NHS Foundation 

Trust form the largest Comprehensive 

Cancer Centre in Europe, and one 

of the largest in the world, which 

has an outstanding national and 

international reputation. Our 

mission, "to relieve human suffering 

by pursuing excellence in the fight 

against cancer", is carried out within 

a framework of activities in research 

and development, education and 

training, and the treatment and care 

of people affected by cancer. 

Our clinicians and scientists 

collaborate through the Joint Research 

Committee on research strategy and 

priorities. Recent developments 

supported by the hospital and The 

Institute include investment in 

academic surgery with the newly 

established Paul Hamlyn Chair of 

Surgery, held jointly between the Royal 

Marsden, The Institute and Imperial 

College by Professor Sir Ara Darzi, the 

highly successful performance of the 

Oak Foundation Drug Development 

Unit and investment in a PET/CT 

scanner to support imaging research 

and the Drug Development 

Programme. We work, like other 

world-class centres of excellence, in 

a truly international context and in 

partnership with many research 

institutions and funding agencies. 

Oak Foundation Drug Development Unit 

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Molecular 

pathology 

Cancer genes 

Genetic 

epidemiology 

Therapeutics 

Scientific Strategy: 

from cancer genes 

to patient treatment 

and prevention. 

Prognostics 

Diagnostics 

Biomarkers 

Aetiology 

Response to 

therapy 

Targets 

Drugs 

Imaging 

Targeted 

therapy and 

Prevention 

The availability of the sequence of 

the human genome, and of the 

many other genomes which help 

us to understand the meaning of the 

blueprint that makes each of us, has 

enormous implications for cancer 

research. It means that we can now 

systematically identify all of the genes 

involved in the progression from a 

normal cell to a tumour cell. The 

challenge for the future is to exploit 

this genetic information for the 

benefit of cancer patients and our 

joint scientific strategy seeks to put 

in place the skills and resources 

necessary to do this. This is entirely 

appropriate since it was Institute 

scientists, Professors Peter Brookes 

and Philip Lawley, who, some forty 

years ago, first showed that chemicals 

that cause cancer act by damaging 

DNA, from which our genes are 

made. This heritage continues with 

the Cancer Genome Project, initiated 

by Institute scientists Professor Mike 

Stratton and Dr Richard Wooster, and 

undertaken in partnership with the 

Wellcome Trust’s Sanger Institute. 

It will provide us, for the first time, 

with a complete description of the 

genetic alterations which cause the 

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will target these precisely defined 

molecular abnormalities in the search 

for new and specific anticancer drugs. 

Research highlights 

disease, and the results thus far are 

both exciting and informative. 

Our strategy seeks to exploit this 

information in three areas: genetic 

epidemiology, molecular pathology 

and therapeutic development. In 

genetic epidemiology, information 

from the Cancer Genome Project and 

other genetic analyses will be used in 

very large, population-based studies 

to try to discover the environmental 

and lifestyle factors that contribute 

to the development of cancer. Some 

we know, smoking being the most 

obvious, but for many cancers our 

present understanding of causation 

is rudimentary. Our work in 

molecular pathology will use the 

genetic knowledge to devise not only 

new and more sensitive ways of 

detecting the disease earlier but also 

much more precise ways of staging its 

progression, with consequent benefit 

to patient management. Knowing all 

the mutations in a particular tumour 

will help to identify the molecular 

targets for therapeutic intervention. 

Our strategy in drug development 

The development of new therapies 

for cancer depends upon our 

ever-increasing knowledge of the 

molecular basis of the disease. Many 

of the current generation of drugs act 

by inducing a process known as 

apoptosis, or programmed cell death, 

and a major problem that affects 

their use is that in many advanced 

tumours the molecular pathways 

that mediate apoptosis become 

inactivated, and thus the tumours 

acquire resistance to the therapeutic 

agent. We therefore need a detailed 

understanding of the mechanisms 

of apoptosis so that we can overcome 

this resistance to drugs, and to 

radiotherapy. Pascal Meier, a young 

investigator in the Breakthrough 

Toby Robins Breast Cancer Research 

Centre, who was recently granted a 

non-time-limited appointment to 

The Institute’s Faculty, has been 

making significant contributions to 

this endeavour. His research focuses 

on a family of proteins called IAPs 

(for Inhibitors of Apoptosis) which 

play key roles in preventing the 

activation of the death pathway in 

healthy cells. His work has shown that, 

contrary to previous understanding, 

different members of the IAP protein 

family work by quite different 

mechanisms thus exposing further 

complexity in the process which can 

hopefully be exploited to overcome 

resistance to therapy. 

An excellent example of how 

increased understanding of the 

molecular basis of cancer can rapidly 

lead to new therapeutic approaches 

is provided by work led by Alan 

Ashworth, the Director of the 

Breakthrough Centre, in collaboration 

with the biotechnology company 

KuDOS Pharmaceuticals, which is now 

a subsidiary of AstraZeneca. Some ten 

6


Crystal structure of 

the dimeric HSP90 

chaperone in the 

closed ATP-bound 

state (blue and gold 

molecules), in 

complex with the 

p23 regulatory cochaperone 

(red and 

green molecules), 

which only binds 

to HSP90 in this 

conformation. 

The crystal 

structure shows 

how HSP90 utilises 

ATP in its activation 

of client proteins 

such as oncogenic 

protein kinases, 

and explains why 

HSP90 ATPase 

inhibitors prevent 

this. 

years ago he, and Mike Stratton, 

Chairman of the Section of Cancer 

Genetics, succeeded in isolating the 

breast cancer susceptibility gene 

BRCA2. The new work shows that 

tumours carrying mutations in 

BRCA2, and BRCA1, which render 

the cells deficient in a particular 

pathway for repairing damage to 

DNA, are exquisitely sensitive to 

drugs which inhibit the enzyme 

poly-ADP-ribose polymerase, itself 

a component of another repair 

pathway. These drugs have now 

entered Phase I clinical trials in the 

Oak Foundation Drug Development 

Unit of the Royal Marsden with a 

rapidity that exemplifies the value 

of collaborations between our 

scientists and clinicians and the 

biotechnology industry. 

The outstanding success of the 

Breakthrough Centre over the six 

years since its inauguration has been 

recognised by The Institute, and by 

Breakthrough Breast Cancer, in the 

signing of a new agreement which 

allocates additional space in the 

Chester Beatty Laboratories to the 

Centre so that two additional teams 

of breast cancer researchers can 

be recruited. 

The Institute’s Structural Biology 

Initiative continues to be an 

outstanding success. David Barford, 

Co-Chairman of the Section of 

Structural Biology, has made 

significant progress in elucidating the 

structure of the Anaphase Promoting 

Complex. This large molecular 

machine is involved in destroying key 

proteins at precise points in the cell 

cycle, and thus plays an essential role 

in a process which is almost always 

deregulated in tumour cells. There 

has recently been great excitement 

throughout biology at the discovery 

of a totally new mechanism for 

regulating gene expression which 

involves small RNA molecules called 

microRNAs. These act to cause either 

the degradation of mRNAs, or to 

block their translation, and there 

is highly suggestive evidence that 

these processes play a role in cancer. 

Barford’s group have determined 

the structure of one of the key 

components of the degradation 

pathway thus revealing many details 

of the mechanism. 

Meanwhile, Laurence Pearl, the 

other Co-Chairman of the Section, 

has completed a decade long project 

to determine the entire structure of 

the molecular chaperone HSP90. His 

work has provided important new 

information on the mechanism by 

which it facilitates the proper folding 

of many proteins involved in tumour 

7


cell growth. HSP90 is a key target of 

The Institute’s drug development 

programme and clinical trials of the 

inhibitor 17-AAG have given highly 

encouraging results which strongly 

support the notion that blocking the 

action of the chaperone will be 

beneficial. Even more importantly, 

a new, small molecule inhibitor, 

developed by Paul Workman and his 

colleagues in the Cancer Research UK 

The Sir Richard Doll Building 

Centre for Cancer Therapeutics, in 

collaboration with the biotechnology 

company Vernalis, has been licensed 

to Novartis, one of the world’s largest 

pharmaceutical companies, who have 

announced that they intend to rapidly 

take it into clinical development. 

Over the last eighteen months, three 

anticancer drugs developed in the 

Centre for Cancer Therapeutics have 

been licensed to major pharmaceutical 

companies. In addition to the HSP90 

inhibitor, molecules which block the 

action of Protein Kinase B, also 

known as AKT, developed in 

collaboration with the biotechnology 

company Astex, have been licensed to 

AstraZeneca, while inhibitors of PI3 

Kinase, which acts in the same signal 

transduction pathway, developed 

with PIramed, a company which 

The Institute helped to found, have 

been licensed to Genentech. It is 

noteworthy that two of these three 

programmes depended on extensive 

input from the structural biologists. 

To achieve three such deals in such 

a short space of time is extraordinary, 

and is a great tribute to the quality 

of The Institute’s science, and to the 

efficiency and skill of its Enterprise 

Unit, without which we would not be 

able to engage so effectively with our 

industrial collaborators. 

In order to further strengthen our 

work in Structural Biology we have 

recruited three new Faculty members 

who work in this area, and have 

invested significant amounts of 

money in a new Cryo-Electron 

Microscopy facility which will allow 

us to study the structures of the very 

large protein complexes that mediate 

most of the key processes within a cell. 

While the treatment of cancer will 

remain a high priority for the 

foreseeable future, in the long term 

we need to understand what does, 

and does not, cause the disease, so 

that we can develop effective 

strategies for its prevention. In order 

to increase our capacity to undertake 

both such epidemiological studies, 

and work on large-scale clinical trials, 

The Institute has opened a new 

building on its Sutton campus. This 

will be called the Sir Richard Doll 

building in memory of the preeminent 

epidemiologist of the 

twentieth century, who served as 

Chairman of The Institute from 1977 

to 1987, and who sadly died in July 

2005. Tony Swerdlow, Chairman of 

the Section of Epidemiology, led a 

8


major international collaboration to 

investigate whether mobile phone use 

increases the risk of brain tumours. 

The conclusion was that it does not. 

Such studies must be revisited and 

updated but they are of great value 

in allowing individuals to rationally 

evaluate the risks that they face. 

More accurate, and earlier, diagnosis 

of cancer remains a major priority, 

and this is particularly important for 

prostate cancer because we need to be 

able to identify those men to whom it 

is an immediate threat, so that they 

can be treated, and those who will 

live a normal life for many years, 

requiring only careful monitoring. 

Colin Cooper, Chairman of the 

Section of Molecular Carcinogenesis, 

has continued his important work to 

identify markers which allow this 

distinction to be made, and has added 

HOXB13 to the list of such markers 

that merit detailed clinical evaluation. 

He has also made a very important 

technical contribution by developing 

a method for making tissue arrays 

from prostate needle biopsies. The 

rather simple device that has been 

developed will make it enormously 

easier to use large numbers of the 

newly developed markers to build 

up a comprehensive assessment 

of the likelihood that the disease 

will progress. 

It is now clear that screening the 

population for some cancers, for 

example breast and cervical, can be 

highly beneficial and it is therefore 

important to develop more accurate 

and sensitive screening procedures. 

Women who carry mutations in 

BRCA1 or BRCA2 are at extremely 

high risk of contracting breast, and 

ovarian, cancer at a young age. 

Conventional, mammographic, 

screening procedures do not work so 

well on younger women because their 

breasts are dense, so there is a clear 

need for an alternative method. 

Martin Leach, Co-Director of the 

Cancer Research UK Clinical Magnetic 

Resonance Research Group, led a 

major national trial, funded by the 

Medical Research Council, to explore 

the use of magnetic resonance 

imaging (MRI) for this purpose. The 

MARIBS trial showed that MRI is 

much more effective in such younger 

women and it is to be hoped that 

this new screening modality will 

become widely available to women 

at high risk. 

2005 was a landmark year for results 

from clinical trials of targeted 

biological therapies in solid cancers 

which will change clinical practice, 

and senior researchers from the Royal 

Marsden and The Institute played a 

significant part in three key 

developments. Sorafenib was 

originally developed for its ability 

to inhibit C-RAF, but it has multiple 

targets including the vascular 

endothelial growth factor receptor 

(VEGFR). Tim Eisen and Martin Gore 

from the Renal Unit conducted a 

randomised trial in conjunction with 

US colleagues which showed that the 

drug was effective as second line 

therapy, and this was subsequently 

confirmed in a larger multi-centre 

international trial. In December 2005 

Sorafenib received a license for 

advanced renal cell cancer based on 

the data generated from these two 

studies in which The Institute and 

Royal Marsden played a major role. 

David Cunningham from the GI Unit 

led a randomised international trial of 

the monoclonal antibody cetuximab 

targeted against the epidermal growth 

factor receptor (EGFR) which is overexpressed 

in 60-80% of colorectal 

cancers. The results showed that the 

addition of cetuximab to irinotecan 

chemotherapy improved tumour 

response rates and time to disease 

progression compared with cetuximab 

alone, leading to this new treatment 

being licensed for irinotecanrefractory 

metastatic colorectal cancer. 

At the American Society of Clinical 

Oncology meeting in June 2005 

dramatic results were announced from 

three pivotal international trials of the 

monoclonal antibody trastuzumab 

(Herceptin) which targets the growth 

factor receptor HER2 that is overexpressed 

in 20% of breast cancers. 

These trials showed that the addition 

of Herceptin to chemotherapy for 

early breast cancer reduced the rate of 

recurrence by 50%, representing the 

single biggest improvement in 

outcome ever seen for any adjuvant 

drug therapy in breast cancer. Ian 

Smith from the Breast Unit led the 

UK’s involvement in the HERA trial 

through The Institute's Clinical Trials 

Unit. 

Radiotherapy research has focussed 

on the development of new 

techniques that can then be adopted 

more widely in the NHS. In prostate 

9


cancer, the Urology Unit has 

continued its work in conformal 

radiotherapy with the introduction 

of a quality assurance programme 

that has now allowed the technique 

to be taken up by 50% of the UK’s 

radiotherapy units. A similar 

approach is now underway with 

intensity modulated radiotherapy, 

and the current CHHIP trial that 

was started at the Royal Marsden by 

David Dearnaley has now expanded 

to ten other UK centres. This study 

explores the use of shorter hypofractionated 

radiotherapy courses 

which if successful would mean 

a much better utilisation of scarce 

radiotherapy resources. On behalf 

of the Breast Unit John Yarnold 

presented the final 5-year results of 

the RMH Breast Radiotherapy 

Dosimetry Trial in October 2005, 

which confirm that 3D intensity 

modulated radiotherapy reduces the 

risk and severity of late radiotherapy 

adverse effects in the breast. These are 

the first randomised data relating to 

this technique of breast radiotherapy 

(developed at The Institute and the 

Royal Marsden in the late 1990s) and 

underpin the introduction of this 

technique UK-wide. 

News of our staff and 

their achievements 

The Chairmen and the Chief Executive 

of The Institute offer their warmest 

congratulations to Cally Palmer, the 

Chief Executive of the Royal Marsden, 

who was awarded the CBE in the New 

Year Honours List for services to the 

NHS. This is an enormously well 

deserved recognition of her 

outstanding contributions to the 

treatment and care of cancer patients, 

and to research and education. 

We were all absolutely delighted that 

David Barford, Professor of Molecular 

Biology and Co-Chairman of the 

Section of Structural Biology, was 

elected to the Fellowship of the Royal 

Society. This is the highest honour in 

the British scientific system and is a 

great tribute to his outstanding 

research into the mechanisms which 

control the growth of cells. It is 

failures in these mechanisms which 

underlie cancer and Professor Barford's 

work has greatly influenced the 

development of new anticancer drugs. 

Alan Horwich, Chairman of the 

Section of Radiotherapy, stood down 

as Director of Clinical Research and 

Development for the Royal Marsden 

and The Institute at the end of 

September, consequent upon his 

appointment as Academic Dean of 

The Institute. He had undertaken this 

role with great distinction for eleven 

years, and was instrumental in 

maintaining the Trust’s income from 

NHS R&D. He is succeeded by 

Stephen Johnston, Consultant 

Medical Oncologist for the Breast 

Unit, to whom we wish every success. 

He faces new challenges as we seek to 

respond effectively to the Department 

of Health’s new Research Strategy. 

Janet Husband, Professor of 

Radiology, has been elected Vice-Chair 

of the Academy of Medical Royal 

Colleges, and was awarded the Gold 

Medal of the European Association 

of Radiology. Ian Judson, Professor 

of Clinical Pharmacology and Head 

of the Sarcoma Unit, has been elected 

President of the British Sarcoma Group. 

Financial facts and figures 

The principal sources of income 

and the expenditure of our joint 

institution are summarised in the 

Facts and Figures 2005 illustration on 

p.12. Full and detailed statements of 

the financial accounts of The Institute 

of Cancer Research (for the year 

ended 31 July 2005) and The Royal 

Marsden NHS Foundation Trust (for 

David Barford FRS FMedSci 

10


the year ended 31 March 2006, to be 

published in September 2006) and 

The Royal Marsden Hospital Charity 

(for the year ended 31 March 2006, to 

be published September 2006) are 

separately recorded in our respective 

Annual Reports and Accounts. In the 

financial year ending on 31 March 

2006, the Trust met its key financial 

objectives and achieved a budgeted 

surplus. In the financial year ending 

on 31 July 2005, The Institute 

achieved a balanced budget on 

unrestricted funds after transfers. Its 

expenditure on research grew by 

11.1% from the previous year, with 

increases in spending across a number 

of Sections. 

Overall, the combined annual 

turnover of our organisation 

was £230 million, with 91% of 

this total being devoted to 

research activities and patient 

care services. 

Government funding for our joint 

research activities contributes 38% 

of the total resources for research. 

Our success rate in competing 

for research funding from external 

sources continues to be outstanding, 

at 77% of all applications for peerreviewed 

grants to medical charities 

and government funding agencies. 

The Institute is particularly indebted 

to its major funding partners: 

Cancer Research UK, Breakthrough 

Breast Cancer, Leukaemia Research, 

the Wellcome Trust, the Medical 

Research Council, the Department of 

Health, and many other medical 

research sponsors. 

Commercial partners collaborating 

with The Institute and supporting 

clinical trials at the Royal Marsden 

during 2005 included Novartis, Pfizer, 

GSK, Sareum, Bayer, Cougar, Elekta 

and Synarc. 

Many organisations also contribute 

support by providing funds for 

studentships at The Institute and 

clinical fellowships at the hospital. 

The Royal Marsden and The Institute 

are grateful to all the numerous 

organisations and supporters who 

have made investments in our 

research activities. 

Fundraising 

The Institute is extremely grateful to 

all its supporters for joining us in the 

fight against cancer. It is only with this 

support that we can hope to achieve 

our objective that one day people will 

be able to live free from the fear of 

cancer as a life threatening disease. 

Our Everyman Male Cancer Campaign 

continues to gain momentum through 

the media and our wide range of 

corporate partnerships. High profile 

supporters included Topman, Tesco, 

Cosmopolitan Magazine, The Football 

Association and Professional 

Footballers’ Association amongst 

others, plus we have seen continued 

success with our annual fundraising 

initiative TacheBack, now in its third 

year. We would like to thank all those 

who have contributed to our 

continuing success, including Rotary 

International in Great Britain and 

Ireland, The Grand Charity of 

Freemasons, The Clothworkers’ 

Foundation, Will for Free law firms 

and the many friends and individuals 

who have supported our work through 

donations, the organisation of events, 

or attendance at fundraising occasions. 

We continue to be one of the most 

cost-effective cancer research 

organisations in the world with over 

90% of our total income going directly 

into research. 

In February 2006, the Royal Marsden 

Cancer Campaign reached its £30 

million Make Our Day appeal target, 

for six major projects within the 

hospital. Of these, four had already 

been achieved; a specialist Critical 

Care Unit, a combined PET/CT 

scanner, the Oak Foundation Drug 

Development Unit, and a Medical Day 

Unit. New operating theatres are under 

construction and a Diagnostic Centre 

for the Chelsea site is in the planning 

stages. Many generous gifts from 

major benefactors, trusts and 

companies were augmented by the 

efforts of volunteer fundraisers and 

the families and friends of patients 

and their well-wishers, as well as the 

hospital's staff and the general public. 

We are immensely grateful to all those 

who have contributed to the success 

of the Make Our Day appeal. Support 

for the general charitable funds of 

the hospital, including the purposes 

of research, and staff and patient 

amenities, continues to be actively 

sought and carefully distributed. 

New major appeal projects are in the 

planning stage. 

It is a great pleasure to present this, 

our joint Annual Research Report for 

2005. We pay tribute to everyone who 

has contributed to our achievements 

this year, not least our outstanding 

scientists and clinicians whose 

excellence and dedication keep The 

Royal Marsden NHS Foundation Trust 

and The Institute of Cancer Research 

at the forefront of world-class cancer 

research. 

Tessa Green Lord Ryder 

Chairman 

Chairman 

Cally Palmer Professor Peter Rigby 

Chief Executive Chief Executive 

The Royal Marsden The Institute of 

NHS Foundation Trust Cancer Research 

11

FACTS AND FIGURES 2005 

FACTS AND FIGURES 2005 

Human 

Resources 

Financial Summary 

Income £m Expenditure £m 

Total staff numbers 3,163 

(includes 15 part-time students) 

Cancer Research UK 19.0 

89.0 Research & Development 

and Academic Activities 

Breakthrough Breast Cancer 4.4 

D 

E 

A 

Leukaemia Research 0.9 

Other Charities 5.6 

Medical Research Council 1.6 

Other Government (UK, EU, US) 6.0 

Industry & Commerce 5.1 

Private Patients 29.4 

C 

B 

Legacies & Donations 13.4 

Investments & Property 6.6 

Other Income (inc Capital) 16.1 

118.1 Patient Care & Treatment 

A 27.3% Scientific Staff (862) 

B 28% Central Support (887) 

C 16.9% Medical Care (534) 

D 22.8% Nursing Care (722) 

E 5% Students (158) 

Higher Education 

Funding Council 12.0 

NHS Executive (R&D) 24.1 

NHS (Patient Care) 85.8 

1.6 Fundraising 

6.5 Administrative Support 

11.9 Capital Development 

& Development Fund 

0.8 Other Expenditure 

12 

Total: £230.0 million 

£227.9 million 

(The Royal Marsden’s figures are provisional and unaudited for the year end 31/03/2006)

ACADEMIC DEAN’S REPORT 2005 

ACADEMIC DEAN’S 

REPORT 2005 

During 2005, in its second year as a College of the University of London, The Institute had 

another outstanding academic year. We have seen the successful continuation of our 

established academic activities as well as a number of important new strategic initiatives. 

In particular, we congratulate our newly appointed professors and qualifying students. 

Alan Horwich 

PhD FRCR FRCP FMedSci 

Alan Horwich is Professor of 

Radiotherapy and the 

Academic Dean of The Institute 

of Cancer Research 

The Faculty, Teachers 

and Awards 

The achievements of our senior 

scientists and clinicians continue to 

be recognised by the conferment 

of academic titles of the University 

of London. The title of Professor 

of Molecular and Population Genetics 

was conferred upon Richard Houlston 

and the title of Reader in Cell Biology 

was conferred upon Pascal Meier. 

Nazneen Rahman was appointed to 

the established chair of Childhood 

Cancer Genetics. Dr Tim Eisen, 

Dr Richard Lamb and Dr Eric So were 

granted recognition as Teachers 

of the University of London. The 

title of Emeritus Professor was 

conferred upon the former Academic 

Dean, Professor Bob Ott. 

Conferences, lectures 

and seminars 

A highlight of The Institute’s 

academic year is the annual Institute 

Conference, an event which aims to 

share knowledge and expertise across 

The Institute and Royal Marsden 

NHS Foundation Trust, and to 

encourage collaboration in research. 

Staff and students contribute in 

a variety of ways, and the blend of 

lectures, student presentations, and 

team poster presentations, display 

the breadth of research in The 

Institute and the Royal Marsden. 

The sessions of this year’s Institute 

Conference, held at the University 

of Surrey, were entitled: A Crossover 

Tour of Physics and Biology 

(Chair: Dr Kathy Weston); Chemistry 

(Chair: Dr Ted McDonald); 

Clinical Session (Chair: Professor Bob 

Ott); Epidemiology and Clinical 

Trials (Chairs: Professor Tony 

Swerdlow and Professor Judith Bliss); 

Late Breaking Publications (Chair: 

Professor Keith Willison); and finally 

Structural Biology (Chair: Professor 

Laurence Pearl). A new addition this 

year was two workshop sessions 

chaired by Dr Jeff Bamber and Dr 

Pascal Meier. 

Student oral presentations were 

chosen by submission of abstracts and 

were of customary high quality. The 

Third Year student poster prizewinner 

was Giorgia Vicentini, with Katrin 

Gudmundsdottir and David Mason 

as runners-up. 

The Institute’s Distinguished 

Lecture Series continues to attract 

outstanding scientists of international 

renown. Notable lectures this year 

included: ‘From embryonic stem cells 

to neural stem cells’ (Professor Austin 

Smith, The Institute for Stem Cell 

Research, University of Edinburgh); 

‘Invasive growth: A genetic program 

linking coagulation to metastasis’ 

(Professor Paolo M Comoglio, 

Institute for Cancer Research, Torino, 

Italy); ‘Mouse models for cancer’ 

(Dr Anton Berns, Division of 

Molecular Genetics and Center of 

Biomedical Genetics, The Netherlands 

Cancer Institute, Amsterdam); 

‘Towards image guided radiotherapy 

13


Research degree students 

Graduands in the Brookes Lawley Building 

with ‘smart’ non-toxic biological 

agents’ (Professor Harry Bartelink, 

Department of Radiotherapy, 

The Netherlands Cancer Institute, 

Amsterdam); and ‘Regulating 

craniofacial and bone development’ 

(Dr Robb Krumlauf, Stowers 

Institute for Medical Research, 

Kansas City, USA). 

This year’s Link Lecture, which took 

place in September, was given by Dr 

Sanjiv Sam Gambhir of the Department 

of Radiology at Stanford University and 

was entitled ‘Seeing is believing: 

Molecular imaging in living subjects’. 

The Inter-site Lecture Series, designed 

to foster greater links between the 

Chelsea and Sutton campuses, continues 

to go from strength to strength. These 

complement the large numbers of 

seminars with external speakers that are 

organised by individual Sections. 

The Graduate School 

A major strategic development in 

2005 was the institution of the 

Graduate School, established as a 

Corporate Services department 

bringing together the Registry, the 

Interactive Education Unit, and 

the Library and Information Service 

into one integrated academic support 

service. A new Registrar and Director 

of The Graduate School, Mr Simon 

Hobson, was appointed at the end of 

September. The Graduate School is 

based in the Sir Richard Doll Building 

at The Institute’s Sutton campus that 

became operational in October. 

In parallel with the creation of the 

Graduate School, the arrangements 

for the academic management of 

our substantive research degree 

programme were also reviewed and 

an Academic Dean’s Team has been 

established in order to formalise the 

existing processes. The Team meets 

on a monthly basis and, in addition 

to the Academic Dean, comprises 

the following members of The 

Institute’s Faculty: Professor Ann 

Jackman, Deputy Dean (Biomedical 

Sciences); Professor Kathy Pritchard- 

Jones, Deputy Dean (Clinical 

Sciences); Dr Jeff Bamber, Senior 

Tutor (Sutton); and Dr Kathy 

Weston, Senior Tutor (Chelsea). 

Our research degree programme has 

in excess of 100 research degree 

students working on cancer-related 

projects and enrolled on MPhil or 

PhD degrees of the University of 

London. Demand for entry to our 

PhD research training programme 

remained very high with many 

outstanding students from the UK 

and overseas being keen to join 

us. There were 395 applications with 

23 new MPhil/PhD students joining 

in September 2005, including four 

clinical fellows. We have 6 part-time 

MPhil/PhD registrations. In addition 

to those following MPhil and PhD 

degrees, there were a smaller number 

of clinical research students following 

a two-year part-time Advanced 

Degree in Medicine of the University 

of London, the Doctor of Medicine 

(MD). The MD was recently reviewed 

by the University of London and 

from 1 September 2005 the revised 

title of MD(Res) was instituted. 30 

students were registered for the MD 

or MD(Res) at the end of 2005. 

As always we acknowledge and 

thank those organisations that have 

supported our students during the 

past year: AstraZeneca, Breakthrough 

Breast Cancer, Cancer Research 

UK, the Engineering and Physical 

Sciences Research Council, 

the Medical Research Council 

and Leukaemia Research. 

The Award Ceremony took place 

on 28 April in the Brookes Lawley 

Building, Sutton and was attended 

by Professor Sir Graeme Davies, 

Vice-Chancellor of the University 

of London. In total 40 graduands 

received their University of London 

degrees, and of those 32 gained the 

Doctor of Philosophy (PhD); 2 gained 

the Master of Philosophy (MPhil) and 

6 received the Doctor of Medicine 

(MD). The Chairman’s Prize for the 

best graduating PhD students 

was awarded to Dr Geoffrey Charles- 

Edwards and Dr Mathew Garnett. 

14


There were also five conferrals of 

‘Member of The Institute’ and 

nine of ‘Associate of The Institute’. 

New taught 

postgraduate course 

Whilst The Institute’s primary 

educational activity concerns 

research, in order to deliver our 

mission we also need to place 

importance on postgraduate teaching. 

Therefore a major academic 

development this year - that came 

to fruition when the first students 

commenced their studies in March 

2006 - was the policy decision to 

develop a taught postgraduate 

qualification in Oncology. This is 

the first of a possible portfolio of 

courses aimed at educating and 

training the next generation of 

specialist cancer clinicians. A 

validation event was held in 

December 2005 which subjected the 

proposals to intensive peer review 

and resulted in a recommendation to 

the Academic Board that the course 

be approved. 

The course adopts a modular, credit 

accumulation model that will be 

attuned to the specific needs of the 

students. Individual 5 or 10 credit 

modules will be designed to provide 

detailed and distinct skills, together 

with advanced knowledge in a 

particular aspect of Oncology. Taken 

together in defined blocks of 60 

and 120 credits, these credit-bearing 

modules will lead to a coherent 

part-time programme with possible 

exit points at Postgraduate Certificate 

and Diploma level. The final 

research phase, which will require 

the submission of a 20,000 word 

dissertation, or the equivalent 

presentation of scientific papers for 

assessment, will lead to the MSc 

Degree level award. 

We have identified a strong market 

demand for this course which comes 

from UK-based students who are 

working as Specialist Registrars in 

medical specialties following training 

schemes managed by their local 

NHS Deaneries. In the field of 

clinical oncology, a structured 

training programme is necessary 

for entitlement to sit the Part 1 and 

Part 2 examinations for Fellowship 

of the Royal College of Radiologists 

(FRCR). The Institute’s course will 

deliver - in 120 ‘M’ level credits - 

the core curriculum necessary to 

sit these examinations and it is 

expected that all the Clinical 

Oncologists will do so. For Medical 

Oncologists, this course will meet the 

perceived need for an improvement 

in the theoretical basis of their 

structured training. 

In overall terms the course has 

been designed to exploit the existing 

academic profile, specialist facilities, 

research-intensive learning 

environment, and world-class 

academic and administrative staff 

resources at The Institute. It will 

exploit the latest educational tools 

and techniques to deliver a high 

quality, cutting-edge modular taught 

postgraduate course for specialists 

in the field of Clinical and 

Medical Oncology. 

The course will be based at the 

Chester Beatty Laboratories, Chelsea 

and will be led by two Joint 

Course Leaders, Dr Robert Huddart 

(Department of Radiotherapy) and 

Dr David Bloomfield (Brighton and 

Sussex University Hospitals NHS Trust). 

Visitors 

The Institute hosted a typically 

large number of visitors in its 

laboratories during 2005. We are 

fortunate in having the resources 

of the Haddow Fund with which 

to foster important links with the 

international scientific community 

attracted by the excellence of The 

Institute. This year the Haddow Fund 

supported visits from Dr Annette 

Affolter to work with Dr Richard 

Marais, Dr Konstantin Lavrenkov 

Figure 1. The cover of Study Skills: 

A Student Survival Guide 

to work with Professor Mike Brada, 

and Professor Regina Kenen and 

Dr Lovise Maehle to work with 

Dr Ros Eeles. 

Interactive Education Unit 

Catherine Dunbar, Acting Head 

The Interactive Education Unit 

(IEU) was established at The Institute 

in 1999 with the remit to develop 

Web- and CD ROM-based educational 

resources (www.ieu.icr.ac.uk). 

The overarching aim of the IEU is 

to promote and disseminate the 

educational, research and clinical 

activities of The Institute in order 

to improve the treatment, care and 

quality of life of people with cancer. 

The Unit has won a number of 

awards, including a Platinum award 

(the highest accolade) for its website 

in the MarCom creative awards, 

a leading international marketing 

and communications competition. 

IEU projects are developed in 

collaboration with leading scientists 

and clinicians at both The Institute 

and the Royal Marsden. The Unit has 

three key audiences: scientists and 

students, healthcare professionals, 

and patients and the public. 

Examples of projects in each of these 

categories are detailed below. 

15


Scientists and students – 

developing resources to aid 

research/career development 

• The Study Skills Website was launched 

in July 2002 on The Institute’s 

intranet. It aims to provide students 

with a range of transferable skills 

such as time management and 

communication. The website is part 

of The Institute’s strategy to meet 

the skills training requirements for 

PhD students funded by the Research 

Councils. Sections on intellectual 

property and critical reading were 

added to the site in June 2005. 

• Study Skills: A Student Survival Guide 

(see Figure 1) was published in March 

2005. Content from the Study Skills 

Website was adapted and expanded 

into an informative and user-friendly 

handbook, published by John Wiley 

& Sons. It identifies the transferable 

skills research students need to 

progress successfully through their 

PhD and on into their working lives. 

The book is an invaluable aid to 

science-based PhD students across 

the UK. 

• Perspectives in Oncology – the cancer 

science website (see Figure 2a) was 

launched in June 2004 to provide 

students at The Institute with a 

thorough and connected grounding 

in the field of cancer science. The 

site emphasises how discoveries in 

scientific research translate into 

clinical care and highlights how the 

fields of physics, biology, chemistry 

and medicine all contribute to 

understanding, managing and 

treating cancer. The site was 

launched initially with five modules, 

covering causes and prevention 

of cancer, common cancers, 

therapies, genetics of cancer, 

and bioinformatics. A module on 

medical physics was added in July 

2005, with a further four modules 

scheduled to be launched and 

developed in 2006-7. 

Healthcare professionals – 

supporting evidencebased 

practice 

• The A Breath of Fresh Air CD ROM 

(see Figure 2b) is an interactive 

guide to managing breathlessness in 

patients with advanced lung cancer 

and is based on research work 

pioneered at The Institute and the 

Royal Marsden. Over 16,000 copies 

of A Breath of Fresh Air have been 

distributed worldwide since its 

launch in 2001. The program is 

provided free to healthcare 

professionals thanks to generous 

sponsorship from the Diana, 

Princess of Wales Memorial Fund 

Project, Macmillan Cancer Relief 

and Marks & Spencer, and can be 

ordered by calling 0800 9177263. 

A second edition of the program 

is currently being developed and 

is due to be launched mid-2006. 

• RT Plan – the conformal radiotherapy 

website, currently in development, 

will help to educate oncology 

clinicians and trainees in 3D 

conformal radiotherapy planning 

in patients with localised prostate 

cancer. 

• Pain Management CD ROM, 

currently in development, is an 

interactive guide to managing 

pain in cancer and will provide 

a comprehensive overview of 

the subject, featuring case histories 

and tools to use with patients. 

Patients and the public – 

educating them about cancer 

• Relax and Breathe, developed in 

collaboration with Macmillan Cancer 

Relief, is available in both CD and 

audiotape format and features 

practical guidance and exercises on 

relaxation. The resource is designed 

to help people with lung cancer cope 

with their breathlessness, but can also 

be used by healthcare professionals 

wanting to learn and practice 

relaxation. Over 9,500 copies of the 

CD, 3,000 of the audiotape and 1,600 

of the healthcare professionals 

resource pack have been distributed 

so far. Relax and Breathe is available 

free thanks to sponsorship from 

Macmillan Cancer Relief, and can be 

ordered by calling the Macmillan 

Resources line on 01344 350 310, 

specifying the preferred format. 

Figure 2a. A page from the medical physics module of Perspectives in Oncology – the cancer science website 

Figure 2b. A page from the second edition of the A Breath of Fresh Air CD ROM 

16

TECHNOLOGY TRANSFER REPORT 2005 

TECHNOLOGY TRANSFER 

REPORT 2005 

The Institute and Royal Marsden work with commercial partners so that research findings 

can be developed and manufactured for the benefit of patients worldwide. The Director of 

Enterprise outlines the highlights of this technology transfer activity during 2005. 

Susan Bright 

PhD 

Susan Bright is Director 

of Enterprise at The Institute 


The Enterprise Unit at The Institute, 

working together with the Royal 

Marsden, has again had a very active 

and successful year. 

The objective of the Enterprise Unit 

is to facilitate the transfer of research 

outputs to commercial organisations 

that can provide development 

resources. Inventions are thereby 

disseminated to as wide a patient base 

as possible. This technology transfer 

effort focuses primarily on ensuring 

that the route of development chosen 

is capable of delivering maximum 

patient benefit. 

Return of revenue to The Institute 

and the Royal Marsden is a welcome 

additional result of the work of the 

Enterprise Unit. The Unit continues 

to work in partnership with Cancer 

Research Technology Ltd (CRT) who 

take the lead in the commercial 

exploitation of Cancer Research UK 

funded work. The Unit also works 

closely with British Technology 

Group (BTG), the Wellcome Trust and 

other technology transfer 

organisations as appropriate to 

specific projects. 

Astex Ltd (PKB collaboration) 

In 2003 The Institute began a 

collaboration with the drug discovery 

company Astex on the development 

of novel inhibitors of the enzyme 

protein kinase B (PKB). It is 

anticipated that these inhibitors will 

be useful anticancer drugs. Professors 

David Barford and Paul Workman are 

The Institute project leaders for this 

collaboration. The project has been 

successful and several promising drug 

candidates have been identified. In 

2005 Astex secured a licensing 

agreement with AstraZeneca for this 

project. This means that these novel 

anticancer drugs will now be 

developed further by a large 

pharmaceutical company, 

demonstrating the value of the initial 

research programme. 

PETRRA Ltd 

The Institute continues its active 

involvement in the spin-out company 

PETRRA, which was founded to 

develop the novel positron emission 

tomography (PET) camera invented 

by The Institute, the Royal Marsden 

and the Rutherford Appleton 

Laboratory, based on the research of 

Professor Bob Ott. The first clinical 

trial of the camera was successfully 

completed in 2004. In 2005 PETRRA 

completed an investment agreement 

with the Rainbow Seed Fund, thus 

injecting welcome additional cash 

into the company. A new CEO has 

been appointed and PETRRA is 

actively seeking further investment 

and a commercial partner. 

Domainex Ltd 

In 2002 The Institute played a key 

role in establishing the new spin-out 

company Domainex together with its 

partners, UCL and Birkbeck. 

17


Domainex secured investment from 

the Bloomsbury Bioseed Fund. 

Professor Laurence Pearl and Dr Chris 

Prodromou were The Institute’s 

founder scientists. Domainex was 

established to exploit a novel 

technology that enables rapid analysis 

of the structure and function of 

complex proteins and which can be 

applied to a wide range of oncology 

targets. In 2005 Domainex secured a 

second commercial contract and has 

made considerable progress in 

developing the technology. 

Chroma Therapeutics Ltd 

The Institute continues its active 

involvement in Chroma Therapeutics 

which is a spin-out company based 

on work carried out at the University 

of Cambridge and by Professor Paul 

Workman at The Institute. Chroma 

was founded to develop novel 

anticancer drugs directed against 

enzymes involved in the remodelling 

of chromatin. In 2005 Chroma made 

good scientific progress in several key 

programmes. One project, 

investigating the enzyme Aurora A, 

involves an active collaboration with 

Institute scientists including a team 

in the Breakthrough Breast Cancer 

Research Centre. Chroma is now 

based in Oxford, has nearly 50 

employees and is financially sound. 

PIramed Ltd 

In 2003 the company PIramed was 

founded, based on research arising 

from the Ludwig Institute of Cancer 

Research, Cancer Research UK and 

Professor Paul Workman at The 

Institute. PIramed is developing a 

number of drug products principally 

focused on inhibitors of the PI3 

kinase superfamily. In 2005 PIramed 

successfully secured a licensing deal 

with the US company Genentech for 

its lead series of novel drug 

candidates. The Institute was 

instrumental in developing this series. 

PIramed has successfully raised 

investment finance on more than one 

occasion and is now based in Slough 

with over 30 employees. 

Vernalis Ltd (HSP90 

collaboration) 


collaboration with the Cambridge 

based biotechnology company 

RiboTargets (now Vernalis) to develop 

inhibitors of the molecular chaperone 

HSP90, which plays an important role 

in directing the function of many key 

intracellular ‘oncogenic’ proteins. 

Inhibitors of HSP90 can thus affect 

the function of these proteins, 

leading to an anticancer effect. The 

HSP90 project combined the 

resources and skills of both Vernalis 

and The Institute; the lead Institute 

scientists on this programme were 

Professors Laurence Pearl and Paul 

Workman. The collaboration ended 

its first phase in 2004 having 

successfully developed several novel, 

potent HSP90 inhibitors and Vernalis 

secured a licensing agreement with 

Novartis who will take these 

compounds into the clinic. In 2005 

Novartis announced that one of the 

lead compounds had met the criteria 

to be selected as a preclinical 

development candidate. 

BRAF collaboration with the 

Wellcome Trust 


collaboration with the Wellcome 

Trust and Cancer Research UK to 

develop novel drugs to inhibit the 

protein BRAF. The identification of 

BRAF as a cancer target resulted from 

The Institute’s involvement with the 

Wellcome funded Cancer Genome 

Project. The joint venture is managed 

by Institute scientists, the Enterprise 

Unit, CRT and the Wellcome Trust. In 

addition the company Astex joined 

the collaboration in 2004, which is 

being project managed by Dr Richard 

Marais from The Institute. The 

18


collaboration has identified two 

distinct chemical series of promising 

novel BRAF inhibitors. In 2005 the 

science continued to progress well 

and one series of compounds is 

showing great potential. The 

Wellcome Trust is leading the 

commercialisation effort and is 

actively negotiating with a number of 

pharmaceutical companies about 

partnering this project. 

Quinazolines (BTG 

collaboration) 

Professor Ann Jackman has worked 

for a number of years on novel 

quinazoline anticancer drugs. Her 

first success in this area was 

the compound Tomudex which is 

now on the market and earning 

royalties. Other quinazoline drugs 

with different mechanisms of 

action are in development, all in 

partnership with BTG. One of 

these drugs, the compound BGC 

9331, is successfully going 

through a Phase II clinical trial and 

evidence of efficacy has been seen. 

MRI Technology 

Professor Martin Leach’s team has 

developed a number of novel tools to 

help in expanding the role of 

magnetic resonance imaging and 

spectroscopy in both a diagnostic and 

treatment setting. Several patents 

have been filed and there are also a 

number of items of proprietary 

software, including a novel 

workstation for computer-assisted 

diagnosis of breast cancer (MRIBview; 

see article by Professor Martin Leach 

and Dr Nandita deSouza, p.34). The 

Enterprise Unit is actively seeking 

industrial partners for these 

technologies. Agreements have 

already been signed with 

GlaxoSmithKline (GSK) and Synarc. 

Sussex Development 

Services 

A collaboration between Professor 

David Dearnaley and Sussex 

Development Services has led to the 

design and development of a novel 

intracavitary device aimed at 

improving the delivery of radiation 

treatment for patients with prostate 

cancer. Following regulatory approval 

by the Medicines and Healthcare 

products Regulatory Agency (MHRA), 

the device will undergo clinical 

evaluation at the Royal Marsden 

before being taken through to market 

by Sussex Development Services. 

Patents 

In total 16 new patents were filed in 

2005 directly by The Institute or in 

collaboration with other institutions. 

Industrial collaborations 

Commercial partners collaborating 

with The Institute and supporting 

clinical trials at the Royal Marsden 

during 2005 included Novartis, Pfizer, 

GSK, Sareum, Bayer, Cougar, Elekta 

and Synarc. 

19

CANCER GENETICS - CHILDHOOD CANCERS 

CANCER IN CHILDREN 

One in 600 children develops cancer; this equates to 1500 children in the UK 

and 200,000 children across the world developing a malignancy each year. 

Fight for survival 

Andy Pearson 

MD FRCP FRCPCH 

Andy Pearson is Cancer Research 

UK Professor of Paediatric 

Oncology, Section Chairman 

of Paediatric Oncology at The 

Institute of Cancer Research and 

Divisional Medical Director for 

Rare Cancers at The Royal 

Marsden NHS Foundation Trust 

Survival in children with cancer 

has progressively improved over the 

last three decades, so that currently 

75% of patients are cured and are 

long-term survivors (see Figure 1). 

The survival of children with 

hepatoblastoma (a liver tumour), 

for example, has increased from 40 to 

80%. This improvement has been due 

to international multidisciplinary 

trials which are designed, executed 

and analysed by well established 

co-operative groups. 

The United Kingdom 

Children’s Cancer Study Group 

(UKCCSG) is one of the world’s 

leading children’s cancer trial 

groups. 

Despite these advances, childhood 

cancers are still the principal cause of 

death from disease between infancy 

and adulthood in developed 

countries; one in four children do 

not survive their illness. Furthermore, 

Figure 1. Survival of children with malignancy in the United Kingdom from 1962 - 1996 

100 

75 

1992-96 N = 7,194 

1982-91 N = 12,786 

1972-81 N = 13,159 

1962-71 N = 12,021 

% still alive 

50 

25 

0 

0 

5 10 15 20 25 30 35 40 

Years since diagnosis 

20


even when cancer treatment is 

successful, there can be significant 

side-effects ranging from second 

cancers (caused as a result of the 

treatment) to infertility. 

To improve further survival in 

childhood malignancy it is necessary: 

• To make additional improvements 

through clinical trials. Most 

clinical trials in children’s 

malignancy are already carried 

out on an international, mostly 

European, basis. The goal is for 

all children with malignancy 

to be entered into randomised 

clinical trials. To achieve this, 

further collaboration, especially 

with North America, is being 

developed so that for rare childhood 

malignancies there are joint 

international trials. For the 

more common malignancies, 

complementary randomised 

trials can be developed. 

• To understand in greater detail 

the underlying biology of childhood 

malignancy. 

• To develop new anticancer agents 

which specifically target the genetic 

abnormalities that cause childhood 

and young people’s malignancies. 

The joint vision of The Institute 

and Royal Marsden is to 

improve survival for the 25% 

of children with cancer who at 

present die from their disease, 

through the development of 

new anticancer agents which 

specifically target the genetic 

abnormalities that cause 

childhood and young 

people’s malignancies. 

The Paediatric and 

Adolescent Oncology 

Targeted Drug 

Development Programme 

Theme and aims 

Cancer in children and young 

people is different in its biological 

basis from adult malignancy. 

At present, children with cancer are 

treated with drugs that have been 

adapted from compounds developed 

to treat adult cancers. To date, no 

drugs have been made specifically to 

treat childhood cancers and 

internationally there is no centre 

which has a major programme and 

facilities in this area. 

The Paediatric and Adolescent 

Oncology Targeted Drug 

Development Programme at The 

Institute / Royal Marsden has 

been created to fulfil the 

international unmet need in drug 

discovery for children with cancer. 

A central theme of the programme is 

the ‘bench to bedside’ translation 

of laboratory research to clinical 

trials which will ultimately alter 

international practice in paediatric 

oncology. The programme comprises 

target identification, drug discovery, 

preclinical evaluation, preclinical 

and early clinical functional imaging, 

and clinical trials. It is envisaged 

that the programme will further 

improve survival of children and 

young people with cancer. 


Oncology Targeted Drug 

Development Programme 

is a comprehensive approach 

to the identification, 

development and evaluation 

of new targeted therapies in 

paediatric malignancy. 

Figure 2. Annual average number of deaths in children under the age of 15 years in Great Britain from 1997 - 2001 with malignancy 

Leukaemias 32% 

Lymphomas 

5% 

Brain & spinal tumours 30% 

Sympathetic nervous system 11% 

Retinoblastoma 1% 

Renal tumours 3% 

Males 

Females 

Hepatic tumours 

Bone tumors 

1% 

4% 

Soft-tissue sarcomas 10% 

Gonadal & germ cell tumours 

Carcinoma & melanoma 

1% 

1% 

0 

10 20 30 40 50 60 70 80 

Average number of deaths per year 

21


The Programme focuses on 

developing agents for poor prognosis 

paediatric tumours, including 

high-grade glioma (a brain tumour), 

rhabdomyosarcoma (a tumour 

of muscle), poor prognosis Wilms 

tumour (a childhood kidney cancer), 

high-risk neuroblastoma (a tumour 

of the adrenal glands) and high-risk 

leukaemia, as they are the major 

causes of death from malignancy 

at the present time (see Figure 2). 

For example, high-grade astrocytomas, 

a type of glioma, in children and 

young people are associated with 

a very poor prognosis with less 

than 10% of children surviving. In 

addition, these malignancies are one 

of the four major causes of death from 

disease in childhood. Furthermore, 

high-grade astrocytomas are one of 

the very few tumours where there 

has been no improvement in survival 

with the outcome in 2005 being 

identical to that of 1977. Currently, 

there is a lack of active compounds 

for the therapy of these tumours 

with nitrosoureas and temozolomide 

being the only established agents. 

Collaborations 


Oncology Targeted Drug Development 

Programme has very strong 

collaborations with other Sections at 

The Institute and Royal Marsden: 

• Professor Paul Workman in 

the Cancer Research UK Centre 

for Cancer Therapeutics, 

who has extensive expertise 

in drug discovery. 

• Professor Stan Kaye, Professor 

Ian Judson and Dr Johann 

deBono in the Section of Medicine 

and Oak Foundation Drug 

Development Unit, who have 

established expertise in the 

early clinical evaluation of new 

anticancer agents. 

• Professor Martin Leach and 

Dr Nandita deSouza in the Cancer 

Research UK Clinical Magnetic 

Resonance Research Group (see 

article by Professor Leach and 

Dr deSouza, p.34). 

• Dr Janet Shipley in the Section 

of Molecular Carcinogenesis, who 

is characterising novel genetic 

changes in rhabdomyosarcoma. 

• Professor Nazneen Rahman in the 

Section of Cancer Genetics, who is 

studying the genetic predisposition 

to childhood cancer. 

• Professor Mel Greaves, 

Professor Gareth Morgan and 

Dr Faith Davies in the Section 

of Haemato-Oncology, who are 

undertaking molecular studies in 

high-risk leukaemia (see article 

by Professor Greaves, p.44). 

Unique strengths 

Our work is part of the new era of 

drug development, which seeks to 

exploit the newly acquired knowledge 

of the molecular mechanisms that 

drive cancer. There are four unique 

features of the Paediatric and 

Adolescent Oncology Targeted Drug 

Development Programme: 

1. The ability of The 

Institute to design drugs 

against targets present 

in children’s malignancies 

The Institute is unique in having the 

world’s only fully integrated academic 

cancer drug discovery unit and it is 

a key objective over the next decade 

to develop drugs for children’s cancer 

together with the Royal Marsden. 

Identified genes will be evaluated 

at the Cancer Research UK Centre for 

Cancer Therapeutics, with the aim 

of developing new anticancer agents 

for use in children. Genes that have 

been identified by teams working 

at The Institute are related to a range 

of conditions, including infant 

leukaemia (Professor Mel Greaves, 

Section of Haemato-Oncology); 

increased susceptibility to Wilms 

tumour and neuroblastoma (Professor 

Nazneen Rahman, Section of Cancer 

Genetics); rhabdomyosarcoma (Dr 

Janet Shipley, Section of Molecular 

Carcinogenesis and Professor Kathy 

Pritchard-Jones, Section of Paediatric 

Oncology); high-grade glioma 

(Dr Chris Jones, Section of Paediatric 

Oncology), and Wilms tumour 

(Dr Chris Jones and Professor Kathy 

Pritchard-Jones, both Section of 

Paediatric Oncology). 

As multiple pathways are 

involved in cancer 

development, the objective 

is to identify rationally which 

pathways should be targeted 

rather than introduce empiric 

combination therapy. 

For example, Dr Chris Jones (Team 

Leader of the Paediatric Molecular 

Pathology Team within the Section of 

Paediatric Oncology) is engaged in 

the identification and validation of 

novel molecular targets in Wilms 

tumour and high-grade glioma. The 

goal of his work is to identify 

genetic alterations in these tumours 

which can be exploited in 

diagnostic, prognostic/predictive 

and therapeutic settings. 

By using a technique called 

microarray comparative genomic 

hybridisation (see Figure 3), the copy 

numbers of genes throughout the 

human genome are being catalogued 

in Wilms tumour and high-grade 

glioma. By this means genes which 

play a role in childhood cancer can 

be identified. 

Genes have been identified in Wilms 

tumour whose increase appears to 

be linked with an increased risk of the 

tumour returning after treatment. 

22


of chromatin modifying enzymes 

(eg, histone deacetylases, histone 

methyltransferases and Aurora 

kinases) and BRAF inhibitors will 

be examined. 

Figure 3. Comparative genomic hybridisation onto glass microarray slides has highlighted a 

number of novel markers of Wilms tumour relapse 

One of these is the receptor tyrosine 

kinase IGF1R, whose signalling 

pathway is known to be altered 

in Wilms tumour and is thought 

to play a role in resistance to 

chemotherapy in other tumour types. 

The demonstration that there is an 

increase at the DNA, RNA and protein 

levels in recurrent Wilms tumour, 

highlights the potential for novel 

therapeutic strategies aimed at 

blocking the receptor in these cells. 

if so, these new agents will be 

evaluated in childhood cancer. 

Novel phosphatidylinositol 3-kinase 

(PI3K) inhibitors and HSP90 

inhibitors have already been selected 

for evaluation in paediatric 

malignancy. In the future, inhibitors 

3. The ability to undertake 

studies with biomarkers, 

especially those involving 

functional imaging 

It is essential to know when a new 

drug is being evaluated that the 

target which the drug has been 

designed against has been hit 

(modulated). This proof-of-principle 

is vital to establish the optimal 

drug dose and schedule to maximise 

the extent and duration of target 

blockade on cancer cell proliferation 

and survival. The evaluation of 

downstream events that occur after 

interaction of the drug and target 

provides this information. Often, 

these biomarkers involve repeated 

biopsies of the tumour. This is not 

possible in children and therefore 

non-invasive methods are needed. 

The Cancer Research UK Clinical 

Magnetic Resonance Research Group 

has a proven international track 

record in translational cancer research 

Figure 4. CT Scan of an abdomen of a child with high-risk neuroblastoma, one of the major 

causes of death in children's cancer in 2005 

2. The ability to investigate the 

role of drugs developed at the 

Cancer Research UK Centre for 

Cancer Therapeutics in children 

There is an extensive portfolio of 

drug discovery projects at the Cancer 

Research UK Centre for Cancer 

Therapeutics. These projects aim to 

develop drugs against molecular 

targets which are mutated or 

inappropriately active in cancer. 

The first goal is to determine if these 

pathways are implicated in cancer 

development in glioma, 

neuroblastoma (see Figure 4), 

leukaemia and rhabdomyosarcoma; 

23


studies will be provided. The facility 

aims to be a major focus for 

early clinical trials in children from 

London and the South of England. 

Phase I and II clinical trials will be 

undertaken with complementary 

pharmacology and pharmacodynamic 

studies. Functional imaging will 

provide important, non-invasive 

pharmacodynamic endpoints in 

the paediatric population. 

Initially, the Unit will have one inpatient 

bed and up to two day-care 

beds. Clinical care will be provided by 

the Oak Foundation Consultant in 

Paediatric Drug Development, 

Dr Darren Hargrave, the Senior 

Research Nurse responsible for 

Drug Development and the Day 

Unit Nurse responsible for Drug 

Development, together with existing 

consultant, junior medical and 

nursing staff of the Children’s Unit 

at the Royal Marsden. 

Our aim is to expand to a 

four-bed dedicated Oak 

Foundation Paediatric and 

Adolescent Clinical Drug 

Development Unit. 

24 

and has performed preclinical 

magnetic resonance spectroscopy 

(MRS) investigations on a range of 

molecular targeted therapies which 

are now translating through to 

clinical trials. 

The aim is that MRS 

measurements may act as 

non-invasive biomarkers in 

children and that a functional 

(molecular) imaging strategy 

will be incorporated in Phase 

I/II studies of novel agents. 

4. The ability to efficiently 

undertake a large number of 

early clinical trials of new drugs 

in children and young people 

Funding from the Oak Foundation 

has made possible the establishment 

of the Paediatric and Adolescent 

Clinical Drug Development Unit at 

the Royal Marsden in Sutton. When 

fully operational, the Unit will be 

a specific, comprehensive facility for 

the early clinical evaluation of 

new anticancer agents in children 

and young people with malignancy. 

An appropriate clinical research 

environment, intensive psychological 

support and family accommodation 

for children undergoing early clinical 

Hot and future topics in 

childhood cancer 

• The long-term goal is that new 

anticancer agents, which target 

specific molecular pathways, will 

be selected rationally for individual 

patients. Therefore, it is important 

to know if a child’s tumour 

expresses the specific drug target. 

This requires increased links with 

pathology and the development 

of molecular diagnostics. 

• Novel phosphatidylinositol 3-kinase 

(PI3K) inhibitors developed by the 

Cancer Research UK Centre for


Cancer Therapeutics have been 

shown to be active in adult highgrade 

glioma cell lines. Initial 

evidence suggests that the PTEN/ 

PI3K pathway could be very 

important in high-grade gliomas in 

children, a cancer where only 10% 

of children survive. Investigations 

are ongoing to determine if this 

pathway is critical in childhood 

gliomas and to determine the 

activity of PI3K inhibitors in 

childhood high-grade glioma cell 

lines. If the pathway is important, 

early clinical trials evaluating these 

compounds in high-grade gliomas 

in children will be carried out; 

the studies will incorporate 

measurements of biomarkers and 

functional imaging. 

• With the opening of the Oak 

Foundation Paediatric and 

Adolescent Clinical Drug 

Development Unit and the link 

with the Cancer Research UK 

Centre for Cancer Therapeutics, 

it is anticipated that there will be a 

substantial increase in the number 

of new anticancer agents available 

for evaluation in children and 

young people with cancer and the 

number of children entered onto 

early clinical trials. 

• Another way of predicting if a drug 

will work in an individual patient’s 

tumour is by measuring the very 

early response to the drug using 

functional imaging, eg MRS. In this 

way, children will only be treated 

with a drug if it is known that it will 

be effective. By carrying out MRS 

studies a few hours after a drug is 

given and measuring the effects, 

it is hoped to determine if the 

compound is going to be active. 

This is much faster than the current 

methods which require clinical 

tumour measurements 6 weeks after 

the drug has been given. 

25

CANCER BIOLOGY - TARGETED TREATMENTS 

TARGETING CANCER’S 

ACHILLES’ HEEL 

Some people are born with a high chance of developing cancer. 

While most breast cancers are not acquired by inheritance, a few 

percent are genetically determined. 

BRCA genes and breast cancer 

26 

Alan Ashworth 

PhD FMedSci 

Alan Ashworth is Professor 

of Molecular Biology and 

Director of the Breakthrough 

Toby Robins Breast Cancer 

Research Centre at The Institute 


Defective forms of two genes, BRCA1 

and BRCA2, are known to predispose 

individuals to a high risk of breast, 

ovarian and other cancers. The 

chance of getting cancer can be so 

high, up to an 85% lifetime risk, that 

some BRCA mutation carriers elect to 

have the at risk organs, breast and 

ovary, surgically removed to prevent 

these life-threatening diseases from 

occurring. 

So why does having a defective 

version of the BRCA1 or BRCA2 gene 

lead to a high risk of developing 

cancer Ten years of research from 

many labs around the world, 

including our own, has generated 

a wealth of information providing 

insight into this question. Many 

believe that normally these genes 

are important players in protecting 

our genomes from the hostile 

environment to which we are all 

exposed. Our genetic material, 

DNA, is quite a fragile molecule 

that is under continual assault from 

all sorts of chemical stress, 

background radiation, cosmic rays, 

sunlight and dietary factors. In 

fact, it has been established that 

there are 10,000 different bits of 

damage to the DNA in every one of 

the 100,000,000,000,000 cells 

in our bodies every day. Without 

elaborate and efficient mechanisms to 

fix this damage we would not be 

able to survive. 

BRCA1 and BRCA2 appear 

to be critical for the repair of a 

particular type of damage to 

DNA which results in the DNA 

double helix becoming severed. 

When the BRCA1 and BRCA2 

genes do not function properly, 

which occurs in tumours in 

mutation carriers, the ability to 

repair these particular DNA 

breaks is compromised whereas 

other kinds of DNA damage 

repair mechanisms are intact. This 

dysfunction causes the acquisition 

of many other mutations and propels 

cancer development. 

Treatments to target 

BRCA tumours 

It is this very property of BRCA 

defective cells that we have exploited 

in developing new treatment 

approaches. We have done this in 

two ways. First, we asked which 

among the commonly used therapies 

for cancer might be best for the 

treatment of these particular tumours. 

Second, we used our knowledge of 

the specific defects caused by BRCA 

mutations to develop new and 

potentially more effective treatments. 

To address the first question, we 

performed a series of experiments 

comparing the effects of commonly


used chemotherapies on cells that we 

had isolated which contain defective 

BRCA1 and BRCA2 genes. We 

demonstrated some effect of several 

agents but spectacular sensitivity was 

seen to the drug carboplatin. Coincidentally 

this agent was discovered 

at The Institute many years ago and is 

now one of the most frequently used 

cancer drugs in the world. However, 

carboplatin is not commonly used for 

the treatment of breast cancer. 

To test whether carboplatin 

might be an effective treatment 

for breast cancers arising in 

BRCA1 and BRCA2 mutation 

carriers, we established the 

BRCA Trial 1 clinical study. 

The trial, supported by Breakthrough 

Breast Cancer and Cancer Research 

UK, is the world’s first study to test 

a specific treatment for hereditary 

breast cancer. During the study, 

BRCA1 and BRCA2 mutation carriers 

with metastatic breast cancer will 

be treated with either carboplatin 

or docetaxol, considered the ‘gold 

standard’ existing treatment. 

Responses to the drugs will be 

monitored and compared. 

We hope that the trial will resolve 

the issue of whether the sensitivity 

to carboplatin that we see in the lab 

is mimicked in patients in the clinic. 

It will be several years before we know 

which is the best treatment for this 

subtype of breast cancer. 

Nevertheless, we have established the 

principle that testing whether 

genetically different tumours 

should receive distinct and specific 

treatments can be done in a clinical 

trials setting. Furthermore, this trial 

will form the framework for testing 

new therapeutic approaches in this 

subgroup of breast cancers. You can 

read more about the BRCA Trial 1 at 

www.brcatrial.org. 

New therapeutics 

The BRCA Trial 1 will address the 

issue of what is the optimum existing 

treatment for cancers arising in 

BRCA mutation carriers. But can we 

go further and use our knowledge 

of the biochemical defects caused by 

BRCA mutation to design new 

therapeutics Over the last couple of 

years, we have made considerable 

progress in this area. We envisioned 

that a treatment exploiting the 

differences between tumour and 

normal tissue might not only be 

27


Normal cells 

- PARP Inhibitor + 

BRCA2 Mutant Cells 

Figure 1. 

Normal cells and 

cells with mutated 

BRCA2 gene 

treated with PARP 

inhibitor. The drug 

kills the mutant 

cells selectively. 

potentially more effective but might 

be associated with significantly 

reduced toxicity. Our work in this 

area has been a close collaboration 

with KuDOS Pharmaceuticals, a 

biotechnology company based 

in Cambridge, UK. Over several years, 

KuDOS has been developing 

chemicals that block the repair of 

certain kinds of DNA damage. 

We reasoned that, as BRCA mutant 

cells have a specific defect in the 

repair of DNA breaks, blocking other 

kinds of DNA repair with these 

chemicals might have a ‘double 

whammy’ effect on the tumour cells 

but spare the normal tissues. We 

were able to show that chemicals 

called PARP inhibitors, which block 

the repair of a particular kind of 

DNA damage, were spectacularly 

effective at killing BRCA1 and 

BRCA2 defective cells (see Figures 1 

and 2). These cells were around 1000 

times more sensitive than cells with 

functional BRCA1 and BRCA2. This 

enormous difference is hugely 

promising for the effectiveness of 

these agents and the potential for 

minimal side effects. 

Cell Survival 

O 

-1 

-2 

-3 

-4 

BRCA2 normal 

BRCA2 defective 

O 1O -9 1O -8 1O -7 1O -6 1O -5 1O -4 

PARP inhibitor concentration (M) 

One reason that made 

the discovery that PARP 

inhibitors were very 

effective in killing BRCA 

defective cells so exciting 

was the potential for 

rapid clinical development. 

These drugs are already being 

tested in a Phase I clinical trial at 

The Institute in collaboration with 

KuDOS. This type of clinical trial 

tests safety and determines the 

appropriate dose. We are hoping 

that a trial of effectiveness in BRCA 

mutation carriers will begin during 

2006. Of course the infrastructure 

28


that we have developed for the BRCA 

Trial 1 described above will be 

very helpful in testing whether PARP 

inhibitors are useful drugs for the 

treatment of cancers in BRCA carriers. 

Future strategies 

We are very interested in pursuing 

whether similar ‘double whammy’ 

strategies can be used to treat cancers 

arising in individuals who are not 

BRCA carriers. The issue is: do other 

cancers have analogous Achilles’ heels 

that we can target We have some 

evidence that this is likely to be the 

case and that some tumours might 

display ‘BRCAness’, that is they seem 

to harbour defects in the ability to 

repair specific kinds of DNA damage. 

The challenge we now face is how 

to identify these cancers and this is 

under vigorous investigation. 

If PARP inhibitors prove to 

be effective in treating cancer 

in BRCA mutation carriers, 

it might be possible to roll out 

this novel therapeutic 

approach into a much larger 

group of cancer patients. 

Figure 2. Chromosomal damage induced 

by PARP inhibitor in BRCA2 mutant 

(highlighted in red) cells. 

29

CANCER THERAPEUTICS - BREAST CANCER 

TARGETED THERAPIES 

FOR BREAST CANCER 

Abnormalities in particular genes have been identified that 

underlie some forms of breast cancer. We are working to develop novel 

therapeutic strategies that exploit these molecular defects. 

Improvements in breast 

cancer treatment 

Targeted antibody therapy 

with Herceptin (trastuzumab) 

Mitch Dowsett 

PhD (left) 

Mitch Dowsett is Professor of 

Biochemical Endocrinology 

and Section Chairman of the 

Academic Department of 

Biochemistry at The Institute 

of Cancer Research. He is 

also Co-Team Leader for 

Molecular Endocrinology, a 

joint team between the 


Biochemistry and the 

Breakthrough Toby Robins 

Breast Cancer Research 

Centre at The Institute of 


Ian Smith 

MD FRCPE FRCP (right) 

Ian Smith is Professor of Cancer 

Medicine and Head of the Breast 

Unit at The Royal Marsden NHS 


Over 40,000 women develop breast 

cancer in the UK annually and 

the number continues to rise each 

year. Encouragingly, however, the 

death rate has been falling steadily 

over the last ten years. One reason 

for this has been the use of medical 

treatments immediately after 

surgery (so-called adjuvant therapy) 

to destroy residual cancer cells. 

Recently, the Royal Marsden Breast 

Unit has been at the centre of 

exciting new drug developments 

in this area. The Unit is committed 

to working together with The 

Institute’s Academic Department 

of Biochemistry and Breakthrough 

Toby Robins Breast Cancer Research 

Centre to develop better treatments 

for women with breast cancer 

through a co-ordinated programme 

of laboratory and clinical research. 

The past year has seen 

substantial progress in 

our mission with the 

announcement of exciting 

results from clinical trials 

in which the Royal Marsden 

has played a major role. 

HER2 is a cell surface growth factor 

receptor that is over-expressed 

in approximately 20% of breast 

tumours; these cancers are 

characterised by relatively aggressive 

disease. Herceptin is a monoclonal 

antibody targeted against the HER2 

receptor (see Figure 1). Early results 

showed that Herceptin can improve 

the survival of patients with advanced 

HER2-positive breast cancer. During 

2005, exciting results were reported 

from four large trials of adjuvant 

Herceptin in early disease. The largest 

of these (designated HERA) involves 

more than 5,000 patients and the 

Royal Marsden has a pivotal role in 

this trial including representation on 

the Executive Committee (Professors 

Mitch Dowsett and Ian Smith). 

All four trials showed that Herceptin 

reduced the risk of early recurrence 

by about 50% and there are already 

indications of a marked reduction in 

mortality. The treatment is very 

well tolerated although there can 

occasionally be heart complications 

in a small proportion of patients 

(0.5% in HERA). It is important 

that the mechanisms of resistance 

to Herceptin are identified so 

that further improvements in this 

therapeutic approach can be 

developed. We are therefore collecting 

tumour tissue from around the 

world, in a project called TransHERA, 

30


Figure 1. HER2 receptor dimer transmembrane signal transduction (A) and its blockage by Herceptin (B) 

A 

Growth Factor 

HER2 

Cell Membrane 

Binding Site 

HER3 

Signal 

transduction 

Tyrosine kinase 

activity 

Gene 

activation 

Proliferation 

B 

Herceptin 

Binding Site 

Cell Membrane 

Signal 

transduction 

Tyrosine kinase 

activity 

Gene 

activation 

Proliferation 

31


Figure 2. The tissue microarray (TMA) process 

a. Tissue Arrayer; 

Recipient block in metal holder, donor block to the side 

b. A 0.6mm diameter core of paraffin wax is removed from the 

recipient block 

c. A core of tumour tissue is extracted from the donor block d. Core of tumour tissue is transplanted into vacant hole 

in recipient block 

Tissue microarray 

e. Tissue microarray stained for HER2 

f. High power core stained for HER2 

32


to make tissue microarrays (see 

Figure 2) and determine which 

molecular factors influence the 

effectiveness of Herceptin. 

Targeted endocrine therapy 

with aromatase inhibitors 

The aromatase inhibitors are a 

new class of endocrine agents which 

act by inhibiting the production of 

oestrogen in postmenopausal women. 

The first clinical studies of the most 

effective of these, letrozole, were 

carried out at the Royal Marsden 

more than a decade ago. It was 

therefore particularly pleasing for 

us when a major new trial (BIG 

1-98), which we helped run, recently 

reported that letrozole was more 

effective than the original gold 

standard, tamoxifen, when given 

as front-line adjuvant therapy 

to patients with early breast cancer. 

Another aromatase inhibitor, 

anastrozole, has shown similar 

superiority to tamoxifen in the ATAC 

trial. Again, the Royal Marsden has 

a major role in this trial and during 

2005 we have collected around 

1,700 tumour blocks from patients 

in the ATAC trial. Our aim is to 

understand better the molecular basis 

of the advantageous action of 

anastrozole and to determine if 

there are subgroups of patients that 

benefit to different degrees. 

Targeted therapies for 

BRCA mutations 

Professor Alan Ashworth’s 

Breakthrough team has been working 

for the last ten years on how inherited 

defects in the breast cancer genes 

BRCA1 and BRCA2 lead to a high risk 

of breast cancer in some women 

with a very strong family history of 

the disease. Their work has also found 

a weakness in a specialised form of 

DNA repair that may be a potential 

‘Achilles’ heel’ of breast cancers that 

form in this way (see article by 

Professor Alan Ashworth, p.26). 

The Breast Unit has been 

collaborating closely 

with Professor Ashworth 

and Dr Andy Tutt on 

the development of novel 

therapeutic strategies to 

exploit the specific molecular 

defects in women with 

BRCA-mutated breast cancer. 

Neoadjuvant/preoperative 

therapies 

For several years, we have been 

pioneering an innovative approach in 

which breast cancer patients receive 

novel chemotherapeutic agents before 

rather than after surgery (so-called 

neoadjuvant or preoperative therapy). 

Collection of serial biopsies of 

individual tumours under local 

anaesthetic enables us to correlate 

early molecular changes with 

treatment; this may be predictive 

of long-term outcome. Normally, 

trials of novel adjuvant therapies after 

surgery require many thousands of 

patients, many years of follow up and 

are extremely expensive to run. 

We are hopeful that our approach will 

identify effective new drugs much 

more quickly. For example, we are 

about to start trials with lapatinib, 

an oral drug with a broader spectrum 

of activity than Herceptin and with 

the potential to help a wider range 

of patients. 

Meanwhile in one of our 

previous trials (IMPACT), we found 

that endocrine therapy switches 

off proliferation to a variable extent 

in individual tumours, as measured 

by the histochemical marker Ki67. 

Long-term results from this trial have 

shown that the level of Ki67 two 

weeks after starting treatment predicts 

for long-term outcome in individual 

patients. During 2006, we hope to set 

up a large national trial, called 

POETIC (Pre-Operative Endocrine 

Therapy - Individualised Care), to test 

this hypothesis further. 

If the POETIC trial proves 

successful, it would allow 

a new and rapid two week 

assessment of whether a 

particular form of treatment 

is going to be effective 

in the long-term for 

an individual patient. 

33

IMAGING RESEARCH & CANCER DIAGNOSIS – MAGNETIC RESONANCE 

MAGNETIC RESONANCE 

AND CANCER 

Functional magnetic resonance techniques have a variety of applications 

including cancer diagnosis, screening, treatment planning and monitoring 

response, and the study of cancer growth. 

Martin Leach 

PhD CPhys FInstP FIPEM 

FMedSci (right) 

Martin Leach is Professor 

of Physics as Applied to Medicine 

and Co-Director of the Cancer 

Research UK Clinical Magnetic 

Resonance Research Group at 

The Institute of Cancer Research 

Nandita deSouza 

MD FRCR FRCP (left) 

Nandita deSouza is Reader 

in Imaging, Co-Director of the 

Cancer Research UK Clinical 

Magnetic Resonance Research 

Group at The Institute of Cancer 

Research and Honorary 

Consultant Radiologist at 

The Royal Marsden NHS 


Diagnosis of cancer 

Magnetic resonance (MR) techniques 

play a major diagnostic role in cancer, 

with significant national resources 

directed towards improving their 

availability. Rapid technological 

advances demand a continuing need 

to assess new MR methodologies and 

implement them in clinical practice. 

With expertise in both 

translational research and the 

clinical applications of MR, the 

Institute / Marsden partnership 

has a pivotal role in developing 

and implementing advances in 

MR at a local and national level. 

Our primary research focus has 

been on refining the role of MR in 

cancer diagnosis and staging. 

We have also been developing 

quantitative methodologies in MR 

imaging (MRI) and MR spectroscopy 

(MRS). Recently, we have focused 

on developing physiological and 

metabolic measurement methods to 

probe the tumour microenvironment, 

validating these against histology 

and in clinical trials. Correlation of 

MR with genetic data is providing 

insights into the function of the 

cancer genome. In addition, the use 

of functional MR techniques has 

allowed us to non-invasively monitor 

the effects of new therapies to 

identify whether they are behaving 

in vivo as they were designed to. 

This is vital to the validation of new 

therapies in early-stage trials. 

Screening women at high 

risk of breast cancer 

Breast cancer: The risk 

Some 10% of breast cancer occurs in 

women from families with a strong 

history of the disease as a result of 

inherited genetic alterations. Recently 

several genes that are mutated in 

familial breast cancer have been 

identified (eg, BRCA1 and BRCA2) 

and it is now possible to test 

individuals for mutations in these 

genes (see article by Professor Alan 

Ashworth, p.26). While 

chemopreventive methods are being 

developed, and bilateral prophylactic 

mastectomy is an option, regular 

surveillance leading to early detection 

should minimise the mortality risks 

to an individual. Annual X-ray 

mammography (XRM) is the standard 

surveillance offered, but is known to 

have limited effectiveness in 

premenopausal women as their 

breasts are often relatively dense and 

thus distinguishing cancer with X- 

rays is difficult. 

34


MRI is a sensitive method 

of assessing breast cancer in 

symptomatic women, and 

has been identified as a 

potential screening method 

for high-risk women, with 

its evaluation being an NHS 

R&D priority in Cancer. 

MARIBS 

We established and hosted the 

Medical Research Council funded 

MARIBS study to test whether MRI 

screening was better than XRM at 

detecting cancer in women at high 

risk of breast cancer. We recruited 649 

women who received both MRI and 

XRM from 22 centres across the 

country, offering annual screening for 

2-7 years. In women either carrying a 

BRCA1 or BRCA2 mutation, or in a 

high-risk family with a 50% chance of 

being a gene carrier, our results 

showed that MRI was almost twice as 

sensitive as XRM in detecting cancer. 

XRM only detected some 40% of 

cancers, whereas MRI detected 77%. 

The combination of MRI and XRM 

detected 94% of cancers, which is a 

good performance for a screening 

test. We were also able to look at 

effectiveness in women with a specific 

gene mutation. In BRCA1 carriers, 

MRI was four times better than XRM 

and XRM did not detect any cancers 

missed by MRI. While the cancers due 

to BRCA1 and BRCA2 mutations differ 

biologically from the normal 

population, we detected a similar 

proportion of small cancers to the 

NHS Breast Screening Programme 

(NHSBSP), and our recall and benign 

surgical biopsy rate per cancer 

detected were similar to the NHSBSP 

(see Figure 1). Cancer Research UK 

has funded a follow on study, to be 

led by Dr Ros Eeles (Section of Cancer 

Genetics), to investigate the 

interaction of MRI appearance and 

genetic status. 

Based on results from MARIBS 

and other recent trials, bodies 

such as the National Institute 

for Clinical Excellence and the 

American Cancer Society 

are considering revising their 

guidelines for surveillance 

of women at high risk of 

breast cancer. 

Figure 1. 

Left hand panel shows orthogonal contrast enhanced 

images through a screen detected cancer (intersecting 

red lines), using software developed in house to display 

the images. The graph to the right shows the rate of 

contrast uptake, displaying the characteristic rapid 

uptake and washout seen in cancer. Below maximum 

intensity projections through both breasts show the 

relationship of the tumour (arrowed) to blood vessels 

in the breast. This Grade 2 9mm node -ve tumour 

was seen by MRI but not by XRM. 

35


Figure 2. A representation of a 

tumour or tissue displaying 

heterogeneous cellularity. The 

mean path length ‘L’ travelled by 

protons in the extracellular fluid 

within a specific observation time is 

much greater in regions of low 

cellularity where random motion is 

not impeded by the presence of 

cellular membranes. 

L 

L 

proton 

highly cellular region 

mean path length L 

proton path 

Imaging tissue cellularity 

and cell death 

Diffusion-weighted MRI 

Diffusion-weighted magnetic 

resonance imaging (DW-MRI) 

provides image contrast through 

measurement of the properties 

of water within tissues. In a highly 

cellular tissue, water cannot diffuse 

far during the MR observation 

period without being blocked by 

cell membranes (see Figure 2). 

Conversely, in cystic or necrotic 

tissues with fewer structural barriers, 

the diffusional path-length of 

extracellular water is longer. Apparent 

diffusion coefficient (ADC) maps, 

derived from DW-MRI, therefore 

provide a non-invasive measure of 

cellularity. In cancer imaging this 

has potential for diagnosis, treatment 

planning and monitoring response. 

This approach is proving valuable, 

as changes in ADC values are 

measurable earlier than conventional 

imaging response indicators. 

DW-MRI can be exploited to 

improve tumour detection 

and differentiate benign from 

malignant lesions. 

DW-MRI and tumour 

detection 

In prostate cancer, we have shown 

that the addition of DW-MRI 

identifies tumour lesions with greater 

A 

certainty than using conventional 

imaging alone (see Figure 3). 

Additionally, the ADC values of 

malignant prostate nodules appear 

to be lower than those of nonmalignant 

prostate nodules; we are 

validating our results with 

prostatectomy (this work is funded 

by the Royal Marsden Hospital 

Charity). We are also exploring ADC 

as a measure of tumour aggressiveness 

in patients opting to have their 

prostate cancer actively monitored 

(Cancer Research UK funded 

surveillance programme led by 

B 

Figure 3. Primary prostate cancer: 

Transverse T2W image (FSE 2096/90 msec [TR/effective TE] (A) and an isotropic ADC map (B) 

at the same level through the prostate apex calculated from images (b = 0, 300, 500, 800 

s/mm2) with diffusion weighted gradients sensitised in 3 planes. The tumour which is poorly 

seen as an ill defined low signal intensity area on T2W (arrow) is clearly demarcated as an 

area of restricted diffusion (arrow) on the ADC map. 

36


Dr Chris Parker - see article by 

Dr Parker, p.51). In contrast, liver 

metastases show greater diffusivity 

(higher ADC) than normal liver 

tissue. We have shown that 

DW-MRI adds confidence to the 

detection of liver metastases when 

used in conjunction with contrastenhanced 

imaging. 

Predicting tumour response 

to treatment 

Quantitative DW-MRI has the 

potential to predict tumour response 

to treatment. In patients with locally 

advanced rectal cancer, low pretreatment 

tumour ADC (indicative of 

highly cellular lesions) predicted a 

greater reduction in tumour size after 

chemotherapy. Similarly in liver 

deposits, we have observed that a 

high pre-treatment ADC (greater 

diffusivity and more necrosis likely) 

predicted for a poor 

chemotherapeutic response. 

Monitoring response to 

treatment 

Experimental studies report that 

an increase in ADC values early 

after treatment initiation is associated 

with cell death and a subsequent 

reduction in tumour volume. In 

clinical studies of breast and liver 

tumours, ADC values also increase 

early in good responders and are 

potentially of value in identifying 

response within a much shorter 

time scale than changes in tumour 

volume. In collaboration with 

the Department of Medicine Drug 

Development Unit, we are 

incorporating DW-MRI into our 

evaluation of the therapeutic 

effects of new drugs. 

The clinical utility of DW- 

MRI will be expanded to 

complement conventional 

functional MR and CT 

measures of response as well 

as modalities such as PET. 

Interrogating tissue 

metabolism non-invasively 

What is MRS 

Magnetic resonance spectroscopy 

(MRS) measures signals from MRvisible 

elements (eg, 1-Hydrogen, 

19-Fluorine, 31-Phosphorus), and 

allows different molecules to 

be identified due to characteristic 

changes in resonant frequency 

that relate to the specific chemical 

structure of the molecule. MRS 

provides a non-invasive window 

on metabolism in vivo as several 

metabolites may be detected in one 

measurement. Our research is focused 

on using MRS to detect metabolic 

alterations associated with inhibition, 

by novel therapeutics, of specific 

pathways that are activated in cancer. 

These MRS changes are being 

evaluated in well-controlled cell 

systems with a view to utilising them 

in forthcoming clinical trials of these 

new agents. 

In collaboration with the Cancer 


Therapeutics based at The Institute, 

we have used MRS to assess whether 

inhibition of specific pathways (eg, 

RAS-RAF-MEK-ERK1/2 and PI3K), 

proteins (eg, HSP90 molecular 

37


PC 

40h 

U0126 

Time (hours) 

U0126 

P-ERK1/2 

2 4 8 16 24 32 40 

-+-+-+-+-+-+-+ 

Pi 

40h 

control 

ppm 

GPE 

GPC 

4.3 3.9 

% control 

Á-NTP 

140 

P-ERK1/2 

120 

PC 

100 

80 

60 

40 

20 

0 

0 5 10 15 20 25 30 35 40 45 

·-NTP 

UDPS 

Time(h) 

‚-NTP 

ppm 

4 -2 -8 -14 -20 

Figure 4. 

In several human cancer cell lines, 

specific pathway blockade with the 

MEK inhibitor U0126 is associated 

with a decrease in the membrane 

precursor phosphocholine (PC), 

which is normally elevated in cancer. 

ABBREVIATIONS 

PC: phosphocholine 

Pi: inorganic phosphate 

GPE: glycerophosphoethanolamine 

GPC: glycerophosphocholine 

PCr: phosphocreatine 

-, - and -NTPs: nucleoside 

tri-phosphates 

UDPS: uridine di-phosphate sugars 

chaperone) or enzymes (eg, choline 

kinase) could trigger metabolic 

alterations that may be used as 

biomarkers of inhibition of those 

pathways in vivo. 

Many signalling pathways 

that promote cell growth and 

survival are deregulated in 

human cancer. Inhibition of 

these pathways forms the basis 

of development of many new, 

targeted anticancer drugs. 

Monitoring pathways involved 

in cell growth 

In several human cancer cell lines, we 

have shown that specific cell growth 

pathway blockade (eg, with the MEK 

inhibitor U0126) was associated with 

a decrease in the membrane precursor 

phosphocholine (PC), which is 

normally elevated in cancer (see 

Figure 4). This decrease was associated 

with inhibition of proteins that are 

normally activated by these pathways 

(eg, phosphorylated ERK1/2 and Akt), 

and preceded the downstream cellular 

consequences of pathway inhibition 

such as cell cycle arrest or growth 

inhibition. 

Monitoring protein inhibition 

PC can be measured in vivo in 

patients, and therefore may be used 

as a non-invasive biomarker to 

monitor the therapeutic action of 

targeted drugs in clinical trials. An 

example of such an approach is in the 

inhibition of HSP90, a molecular 

chaperone important in assembling 

intermediaries in a number of key 

pathways upregulated in cancer. 

Using MRS measurements we have 

shown that inhibitors of HSP90 such 

as 17-AAG cause characteristic 

changes in the phosphorus spectrum 

in cells and in vivo. 

Based on our research, 

clinical MRS has been 

incorporated into two 

continuing early-stage clinical 

trials of HSP90 inhibitors. 

Monitoring cell membrane 

precursor inhibition 

In collaboration with the Cancer 


Therapeutics and the Cancer Research 

38


UK Biomedical MR Group (St George’s, 

University of London), we are also 

investigating whether MRS provides 

non-invasive biomarkers that indicate 

inhibition of the enzyme choline 

kinase (ChoK). This enzyme catalyses 

the formation of membrane precursor 

PC from its precursor choline. Due 

to the elevated levels of PC in cancer 

cells, inhibition of ChoK leads to 

cell death in these cells and thus 

provides a target for anticancer drug 

development. Treatment with a 

specific ChoK inhibitor resulted in 

a decrease in choline-containing 

metabolites that correlated well with 

the decrease in ChoK. 

The future of MR 

Our imaging programme focuses on 

understanding the processes of 

tumour evolution and response to 

treatment by studying cell systems, 

whole tissues, and xenografts, and 

integrating this with our clinical 

studies. We aim to identify the 

molecular signatures of tumours and 

their functional characteristics in 

order to map morphological and 

functional tumour heterogeneity. 

This will allow us to better 

characterise disease, more accurately 

assess response, and will aid 

stratification of patients for targeted 

therapies, leading to a more tailored 

approach to managing individual 

tumours in order to maximise 

treatment safety and efficacy. By 

evaluating whether new treatments 

are acting as intended, these 

techniques will help speed up drug 

development and progress new 

agents into the clinic. The use of 

functional imaging methods will 

then help identify at an early stage 

in treatment whether these new 

therapies are working in individual 

patients. We aim to improve the 

sensitivity and accuracy of our 

techniques by transferring them to 

a new state-of-the-art 3T clinical 

magnetic resonance system. 

39

CANCER BIOLOGY – STRUCTURAL BIOLOGY 

STRUCTURE-BASED 

DRUG DEVELOPMENT 

Structural biology is an advancing discipline that has major 

implications for the streamlined development of novel therapeutics 

for the targeted treatment of cancer. 

Laurence Pearl 

PhD 

Laurence Pearl is Professor 

of Protein Crystallography and 

Co-Chairman of the Section 

of Structural Biology at The 

Institute of Cancer Research 

Genetic and biological 

insights into cancer 

New genetic insights into the biology 

of tumours increasingly allow us to 

pinpoint precisely the genes whose 

mutation or disregulation underlie 

the disorganised and unregulated 

cellular behaviour we recognise as 

cancer. However, knowledge 

of the gene is not enough, and if 

we are going to understand 

how these genetic changes exert their 

effect, and be able to counteract 

them, we have to look at the proteins 

encoded by the affected genes. 

Structural biology and drug 

development 

The techniques of structural biology 

(X-ray crystallography, single-particle 

electron microscopy) can provide 

an unparalleled level of detailed 

information on the structure of 

proteins involved in the aetiology 

Figure 1. 

Crystal structure of PKB/Akt (cartoon) 

with bound ATP (stick model). Knowledge 

of the structure of the ATP-binding 

site facilitated the development of new 

inhibitors in collaboration with Astex. 

40


and treatment of cancer. Knowledge 

of the three-dimensional structure 

of a protein provides enormous basic 

scientific insights into the function 

of that protein. It allows us to define 

its biochemical mechanism, 

understand how it interacts with 

other proteins, RNA, DNA or 

membranes in the cell, and how 

cancer-linked mutations in its 

structure alter its normal function. 

Most importantly for improving 

patient care, knowing the threedimensional 

structure of a protein 

tells us directly how novel drugs 

can inhibit its excessive/ 

unregulated activity. 

Structural biology sits at a key 

interface between basic and 

translational research, and this 

importance is reflected in the 

considerable investment The 

Institute has made in this field 

in the last few years. 

Traditional drug 

development 

Traditional chemotherapeutic agents 

have a broad range of activities in 

the cell, many of which contribute 

to their general cytotoxicity, and 

unpleasant and dangerous side-effects. 

In principle, novel drugs targeted 

at a single protein in the cell should 

only disrupt the pathways involving 

that protein and as such have far 

fewer side-effects. However, developing 

drug molecules with that level of 

specificity and selectivity is far from 

straightforward, as common 

and important targets such as 

protein kinases share many 

biochemical features. 

Conventional approaches to 

achieving selectivity rely on 

medicinal chemists generating a wide 

range of variants around the basic 

Figure 2. Crystal structure of the kinase domain from an oncogenic form of BRAF protein 

(cartoon), bound to the inhibitor Bayer 439006 (stick model). New compounds based on this 

and other inhibitor classes are in development at The Institute. 

chemical composition of a ‘hit’ drug, 

and testing these for their ability 

to inhibit the target protein as well 

as a range of related proteins. By 

retaining those modifications that 

improve efficacy against the target, 

and avoiding those that inhibit 

related off-target proteins, 

the medicinal chemists are able to 

feel their way through a complex 

chemical landscape with the starting 

drug eventually being ‘evolved’ 

to a sufficient degree of efficacy 

and specificity. 

Drug development using 

traditional medicinal 

chemistry can take a long time 

even when there are clear 

structure-activity relationships. 

Advances made by the 

Section of Structural Biology 

at The Institute aim to 

streamline this process. 

41


Figure 3. 

Crystal structure of the nucleotide-binding 

domain of HSP90 (cartoon), bound 

to CCT018159 (stick model) - the first of 

a new class of HSP90 ATPase inhibitors 

discovered at The Institute. 

42 

Advances in drug 

development 

With our expertise in structural 

biology, Institute scientists are able to 

short-circuit the traditional laborious 

drug development approach, cutting 

years off the process. Once a starting 

‘hit’ drug molecule for a particular 

target has been identified, we cocrystallise 

it with the target protein 

and determine the structure of the 

complex. At a simple level, this helps 

validate the original identification 

of the ‘hit’ molecule and confirm its 

identification as an inhibitor. Most 

importantly, it shows us in precise 

atomic detail, which parts of the ‘hit’ 

drug molecule are actually making 

contacts with the target protein, and 

therefore cannot be modified without 

losing efficacy, and which parts of 

the ‘hit’ drug molecule can be 

changed to enhance pharmacological 

properties such as oral availability 

and persistence in tissues. By 

comparing the crystal structures of 

the same ‘hit’ drug molecule bound 

to target and off-target proteins, we 

can also greatly improve specificity, 

by identifying modifications that will 

allow it to bind to the target protein, 

but make it incompatible with the 

off-target proteins. 

Structure-based programmes 

within the Section of Structural 

Biology have already made 

very important contributions 

to the development of novel 

drugs, and have been 

instrumental in moving these 

projects into collaborations 

with the Biotech and 

Pharmaceutical industries. 

Drug discovery and 

development at The Institute 

PKB protein kinase inhibitors 

The serine/threonine protein kinase 

PKB/Akt is a critical component of 

an intracellular signalling pathway 

that exerts the effects of growth 

and survival factors, and plays an 

important role in the generation 

of human malignancy. 

Professor David Barford’s group 

in the Section of Structural Biology 

devised methods to obtain active 

phosphorylated forms of the protein 

and determined its X-ray crystal 

structure (see Figure 1). This paved 

the way for a collaborative drug 

discovery programme with the 


Cancer Therapeutics at The Institute 

(Professor Paul Workman, Dr Michelle 

Garrett, Dr Ian Collins, Dr Ted 

McDonald), and Astex Therapeutics 

Ltd, who employed a combination of


virtual screening, high-throughput 

crystallography and structure-based 

design approaches to identify and 

optimise a number of lead chemical 

series. The collaborative programme 

led to the development of four 

distinct chemical series of highly 

potent and selective compounds. 

The programme has been licensed 

on to AstraZeneca who will take 

it through to clinical development. 

BRAF protein kinase inhibitors 

Collaborative work between the 

Wellcome funded Cancer Genome 

Project directed by Professor Mike 

Stratton (Section of Cancer Genetics), 

and Professor Chris Marshall and 

Dr Richard Marais (Cancer Research 

UK Centre for Cell and Molecular 

Biology) showed that the protein 

kinase BRAF is mutated in 

approximately 70% of malignant 

melanomas and a significant number 

of colorectal, ovarian and papillary 

thyroid cancers, implicating mutated 

BRAF as a critical promoter 

of malignancy. 

In collaboration with Dr Richard 

Marais and Professor Caroline 

Springer (Cancer Research UK Centre 

for Cancer Therapeutics), Professor 

Barford’s group determined the 

structure of the BRAF catalytic 

domain and identified a class of BRAF 

inhibitors that bind to the active 

conformation of the protein (see 

Figure 2). Further lead series were 

developed and crystal structures of 

complexes combined with molecular 

modelling studies have resulted in 

potent inhibitors. 

HSP90 molecular 

chaperone inhibitors 

HSP90 is a ‘molecular chaperone’, 

required for the stable folding 

and activation of a plethora of cell 

regulatory proteins, many of which 

are disregulated and/or mutated in 

cancer. Mutated protein kinases such 

as BRAF and BCR-ABL, which drive 

many types of cancer, are particularly 

dependent on HSP90, so that 

inhibition of HSP90 offers an 

exciting therapeutic approach with 

the possibility of application to 

a broad spectrum of tumour types. 

We determined the crystal structure 

of key parts of the HSP90 protein 

and showed how several natural 

product small molecules could 

act as specific inhibitors of the 

chaperone’s essential ATPase activity 

(see Figure 3). In collaboration with 

Professor Paul Workman and Drs 

Wynne Aherne and Ted McDonald 

(Cancer Research UK Centre for 

Cancer Therapeutics) we developed 

a high-throughput screen for HSP90 

ATPase inhibitors, and identified and 

characterised CCT018159 – the first 

in a novel class of synthetic HSP90 

inhibitors. These new compounds 

were further developed in 

collaboration with Cancer Research 

Technology Ltd and Vernalis, and 

Professor David Barford and crystallography equipment 

have now been licensed to Novartis 

with the prospect of clinical trials 

commencing this year. 

The future of 

structural biology 

The Section of Structural Biology 

at The Institute has undergone 

substantial expansion in the last year, 

with the recruitment of X-ray 

crystallography teams working on 

the structural biology of mitotic 

regulation (Dr Richard Bayliss) and 

chromatin regulation (Dr Jon 

Wilson), and the inauguration of 

the structural electron microscopy 

team led by Dr Ed Morris. The 

facilities, resources and expertise 

we have been able to assemble will 

keep structural biology at The 

Institute at the international forefront 

in both basic research and in its 

translation to patient benefit. 

43

CANCER BIOLOGY – HAEMATO-ONCOLOGY 

SLEUTHING THE CAUSES OF 

CHILDHOOD LEUKAEMIA 

Whilst more biologically directed and less toxic therapy 

is a realistic goal, finding out what causes leukaemia and whether 

it is potentially preventable are critically important issues. 

The challenge 

Mel Greaves 

PhD Hon MRCP FMedSci FRS 

Mel Greaves is Professor of Cell 

Biology and Section Chairman of 

Haemato-Oncology at The 

Institute of Cancer Research 

Acute leukaemia is the major subtype 

of paediatric cancer in developed 

societies. Each year in the UK, there 

are some 500 diagnoses of this disease 

which translates to an accumulative 

risk of around 1 in 2000 (between 

the ages of 0 and 15 years). 

Treatment of leukaemia in children, 

with combination chemotherapy in 

the context of controlled clinical 

trials, has been an extraordinary 

success story. Overall, cure rates are 

now around 80% but with variation 

between different cellular and 

molecular subtypes of the disease. 

Despite this progress, much remains 

to be achieved. 

Some subtypes of leukaemia 

remain refractory to effective 

eradication and high-dose 

chemotherapy is toxic, 

particularly to developing 

infants and toddlers with 

consequent long-term 

collateral damage. 

Decades of speculation on causation 

have spawned a plethora of candidate 

exposures that might be relevant 

(see Table 1). For most of these 

factors, the evidence is at best fragile 

and inconsistent. Given the biological 

Table 1. Postulated causal exposures for leukaemia 

Car exhaust fumes 

Organic dust from cotton, wool or synthetic fibres 

Pesticides 

Natural light deprivation through melatonin disruption 

Ionising radiation 

Non-ionising electromagnetic fields 

Electric fields 

Vitamin K injection at birth 

Hot dogs or hamburgers (depending on whether the 

consumer (patient) was in California or Colorado) 

Artificial, fluorescent light exposure in hospital neonatal 

care units 

Parental cigarette smoking 

Maternal medicinal drug taking (during pregnancy) 

Maternal alcohol consumption (during pregnancy) 

Chemical contamination in drinking water 

Domestic animals 

Infections 

44


Figure 1. 

1 5 10 15 

Age at diagnosis (years) 

diversity of the disease, it is highly 

unlikely that a single cause exists. 

We know that a small fraction (2-5%) 

of cases involve strong inherited 

predisposition and, from previous 

genetic epidemiological research in 

our Section, that infant leukaemias 

with MLL gene fusions almost 

certainly have a unique aetiology 

involving transplacental chemical 

mutagenesis in utero. 

The key question however is 

whether there is a major mechanism 

accounting for the common variety 

of leukaemia, B cell precursor 

acute lymphoblastic leukaemia (ALL), 

that accounts for the marked peak 

incidence of the disease between 

2 and 5 years of age (see Figure 1). 

Research in the Section of 

Haemato-Oncology has taken 

us close to an answer. 

Infection as a trigger 

Speculation that childhood 

leukaemia might have an infectious 

causation is more than 70 years old 

and has been encouraged by parallels 

with virus-associated leukaemias 

in domesticated cats, cattle and 

chickens. Several other human blood 

cell cancers are known to be linked 

to specific viral or bacterial infections. 

To date, however, all attempts by 

us and other scientists to identify 

footprints of transforming viruses 

in childhood ALL, via sensitive 

molecular screening, have been 

uniformly negative. Whilst this could 

be a misleading result, it nevertheless 

encourages an alternative view that 

Figure 2. Working ‘2 hit’ model of childhood leukaemia 

1° 

Initiation 

(common) 

Chr. 

translocation 

/hyperdiploidy 

Covert 

Pre-Leukaemia 

1% 

Gene 

deletion/ 

mutation 

2° 

Transition to 

leukaemia 

(rare) 

AGE 

Birth 

2-15 years 

45


we first proposed back in 1988, 

namely that the causal mechanism 

is an abnormal immune response to 

one or more viral or bacterial species 

(ie, an indirect effect of infection). 

In developing this model, 

we have placed considerable 

emphasis on our laboratorybased 

insights into the 

molecular pathogenesis 

and natural history of 

childhood ALL. 

Our working ‘2 hit’ model, now 

proven by extensive data sets, 

has three critical features (see Figure 

2). Firstly, a bottleneck in the 

development of leukaemia is the 

transition between covert preleukaemia 

and overt malignant 

disease. We know that this occurs in 

only ~1% of cases with pre-leukaemic 

clones. Secondly, an abnormal 

immune response triggers the 

essential second hit. And thirdly, 

an abnormal immune response 

can arise as a consequence of delayed 

exposure to infection in infancy 

plus a skew in response that is 

genetically inherited. This hypothesis 

led to two testable predictions: 

1. that a deficiency of infectious 

exposures in the first year of life 

should increase subsequent risk 

of ALL 

2. that risk should be associated 

with inherited genetic variation 

in immune response genes. 

The key data 

The UK Children’s Cancer Study 

(UKCCS) was a major nationwide 

case/control epidemiological study 

of the possible causes of childhood 

cancer. Our laboratory provided 

the central resource for molecular 

sub-classification of cases (and 

storage of diagnostic DNA). Professor 

Julian Peto and colleagues in the 

Section of Epidemiology were one 

of the nine regional centres for 

administering the very detailed 

questionnaire and for some of the 

important data analysis. 

The UKCCS, the largest 

study of its kind worldwide to 

date, found no evidence to 

implicate ionising radiation, 

non-ionising electric fields 

or electro-magnetic fields in 

the causation of leukaemia. 

We sought two lines of evidence 

that, if positive, would endorse 

an abnormal response to infection as 

a credible explanation. In the first, 

we analysed the association between 

exposure to other children outside 

the home (in playgroups and as 

a surrogate for infectious exposure) 

and risk of ALL. As predicted by our 

‘delayed infection’ idea, we found 

that infants with more social contacts 

(and presumed infections) had 

a reduced risk of ALL (see Figure 3). 

This result has been replicated 

by a California-based case/ 

control study that adapted the 

UKCCS questionnaire. 

Our second testable prediction 

was that susceptibility to ALL should 

Figure 3. Relative risk of lymphoblastic leukaemia 

0.1 1 Relative Risk 2 

Increasing levels of 

social contact in infancy 

p‹0.001 

Inheritance of 

Immune Response Gene 

variant HLA.DPB1 0201 * 

46


be associated with the inheritance of 

particular normal variants (ie, not 

mutations) of critical genes that 

regulate the immune system. 

The starting point for this was to 

interrogate the HLA gene system 

since this is a well-established 

genetically variable locus critical to 

immune response to infection. 

A significant positive association 

with risk of ALL was found with 

a gene variant called HLA.DPB1 0201* 

(see Figure 3). 

These data do not prove our case 

but they greatly endorse its credibility. 

Independent epidemiological data 

collated by Professor Leo Kinlen 

(Oxford University) have similarly 

linked risk of childhood leukaemia 

with social opportunities for 

infection; in his case in the context 

of transient ‘clusters’ of leukaemia 

and population mobility/mixing. 

So what next 

Now that the hypothesis and model 

have accepted credence, the next 

urgent step is to put some flesh on 

the bones. To achieve this, two things 

are essential. Firstly, a more extensive 

genetic analysis of immune response 

genes and risk is needed. A study 

using human genome-based SNP 

sequences for ‘candidate’ genes that 

regulate the establishment of the 

immune response cellular network 

in infancy has been initiated in the 

Section of Haemato-Oncology with 

Professor Gareth Morgan and Dr Zara 

Josephs. The SNP sequences include 

genes for cytokines such as IL-10, 

IL-12 and TGF‚. 

The size of the UKCCS sample 

set provides us with a unique 

opportunity to pin down 

genetic associations of ALL 

with the immune system. 

Secondly, we need to provide a 

mechanistic explanation for how 

an aberrant or dysregulated immune 

response to infection can ‘select’ 

pre-leukaemic cells such that they 

are at high risk of the disease 

precipitating secondary mutations 

(see Figure 2). To this end, Dr Tony 

Ford in our laboratory has developed 

a tissue culture model system 

in which the predominant ALL 

initiating gene (TEL-AML1 fusion 

gene) can be switched on and 

off at will. Using this model, 

a PhD student, Miss Chiara Palmi, 

has already discovered that cells 

expressing this ‘1st hit’ leukaemic 

gene are selectively resistant to a 

growth-inhibiting immune response 

cytokine (TGF‚). 

Other groups in the UK and 

internationally will certainly be 

looking at genetic variation in 

immune response genes (and other 

genes), and consistent associations 

with childhood ALL in large studies 

will be essential. Our team has been 

the only group worldwide exploring 

the molecular pathogenesis of 

childhood ALL from the perspective 

of natural history and aetiology. 

Whilst we will seek to maintain 

our pole position, it is to be 

anticipated and welcomed that 

others will now seek to explore 

this important issue. The potential 

rewards are considerable; the 

identification of the major causal 

mechanism of childhood leukaemia 

and its possible future prevention. 

47

CANCER THERAPEUTICS/CANCER BIOLOGY – SKIN CANCER 

ADVANCES IN 

MELANOMA TREATMENT 

The BRAF protein is a key part of a molecular signalling pathway that enables cells to 

proliferate. The BRAF gene is mutated in 70% of malignant melanoma cases and, 

as such, the protein represents a specific potential drug target. 

Martin Gore 

PhD FRCP (left) 

Martin Gore is Professor of 

Cancer Medicine at The Institute 

of Cancer Research and Medical 

Director at The Royal Marsden 

NHS Foundation Trust 

Richard Marais 

PhD (right) 

Richard Marais is Reader in 

Cell Signalling and Team Leader 

in Signal Transduction in the 


Cell and Molecular Biology at 


Melanoma: The problem 

Malignant melanoma is a serious 

public health problem in that its 

incidence is increasing every decade 

(see Figure 1). Each year, more than 

7,000 patients develop melanoma 

in the UK and there are over 1,500 

deaths. A number of genetic factors 

predispose people to melanoma but 

those with fair hair and skin, multiple 

moles and episodes of severe burning 

in childhood are at most risk. There is 

12 

8 

11.0 

9.9 

9.4 

8.4 

evidence from Australia that sun 

avoidance campaigns and systems 

that allow for the early removal of 

suspicious moles can all help reduce 

the death rate from melanoma. Early 

diagnosis of melanoma is important 

because it reduces the chances of the 

disease progressing to the metastatic 

stage, when it attains the ability to 

disseminate to other sites including 

the vital organs. Metastatic disease 

is particularly difficult to treat 

and has a very poor prognosis, with 

12.4 

7.3 

4 

Males 

Females 

48 

Figure 1. 

Age standardised rates 

of melanoma per 100,000 

population (England) 

1993 

1999 2003


a 5-year survival rate of less than 5%. 

Patients are at risk of disease 

dissemination if they have a thick 

primary lesion or the disease has 

spread to local lymph nodes. 

The Melanoma Unit has 

played a major role in many 

trials of adjuvant therapy 

in high-risk melanoma 

populations using a number 

of therapeutic strategies 

including vaccination and 

interferon therapy. 

Despite our efforts, there is 

still no effective treatment for 

malignant melanoma. The 

results of chemotherapy have been 

disappointing and immunotherapies 

have similarly not shown a survival 

benefit for these patients. For patients 

with the disseminated disease, 

the prognosis remains very poor with 

a median survival of 6 months. 

Treatment of patients once their 

disease has disseminated is palliative, 

and the main focus of the Unit’s 

activity over the last 15 years has 

been to try and develop therapies that 

can impact the metastatic disease. 

Vaccination for melanoma 

Clinicians within the Royal 

Marsden together with scientists at 

The Institute developed the first 

genetically modified vaccine against 

cancer in the UK. This vaccine 

utilised the patient’s own tumour 

cells, and the gene encoding a 

biological factor called interleukin 2 

was inserted into the cells prior to 

vaccination. The study showed that 

patients who developed an immune 

response to the vaccine lived longer 

than those who did not. There were 

two long-term survivors from this 

trial, one of whom has remained 

disease free for nearly ten years. 

Parallel to this trial, the Unit 

worked with colleagues in the 

European Organisation for Research 

and Treatment of Cancer (EORTC) 

Melanoma Group to develop 

new chemotherapy strategies 

that combined conventional 

chemotherapy, interleukin 2 and 

another biological agent, interferon. 

Large randomised trials failed 

to show a benefit for this approach 

and so the Unit together with 

The Institute altered its research 

strategy, with the Unit becoming 

a major contributor to one of 

the largest randomised trials ever 

performed in melanoma. In this 

trial, a new type of drug, called 

an anti-sense molecule, which targets 

a protein called BCL2 (believed 

to be involved in melanoma tumour 

cell survival), was combined 

with conventional chemotherapy. 

This novel approach had some 

minor success in that it extended 

the progression-free survival of 

the patients, but unfortunately, it did 

not impact on overall survival. 

In 2002, our work at The 

Institute, in collaboration with 

colleagues from the Wellcome 

Trust Sanger Institute, led to 

an exciting and unexpected 

discovery that a protein called 

BRAF is mutated in around 

70% of malignant melanomas. 

BRAF and melanoma 

BRAF, a member of a protein family 

called the protein kinases, regulates 

the growth of cells during normal 

functions such as cell development 

and wound healing. Our ongoing 

work at The Institute demonstrated 

that mutated BRAF is locked in the 

active state and therefore it sends a 

continual growth signal to cancer 

cells. This causes the cells to grow in 

an uncontrolled manner and also 

makes them very resistant to death. 

We also demonstrated that the 

activity of mutant BRAF could be 

blocked by sorafenib, a drug that was 

undergoing clinical trials for other 

types of cancer. Sorafenib had been 

developed to inhibit the activity of 

a closely related protein called CRAF, 

and these proteins are sufficiently 

similar that sorafenib also had some 

activity against BRAF. 

Targeting BRAF for 

melanoma treatment 

The Melanoma Unit, in collaboration 

with two other institutions in the 

USA, initiated a number of clinical 

trials to determine if sorafenib 

had activity against mutant BRAF in 

melanoma patients. However, it 

quickly became apparent from work 

conducted with other clinical and 

scientific colleagues at The Institute 

and Royal Marsden that the major 

clinical effect of sorafenib was in 

renal cell carcinoma, a disease that is 

not associated with mutant BRAF. 

This may be because sorafenib is not 

sufficiently potent to directly target 

BRAF in melanoma. Nevertheless, 

there is evidence that sorafenib can 

be combined with other forms 

of chemotherapy to produce some 

responses in melanoma. 


and The Institute have taken 

the international lead in 

developing a combination of 

sorafenib and darcarbazine for 

the treatment of melanoma; 

the potential of this combined 

chemotherapy is currently 

being tested. 

49


scientific findings to the clinic with 

exceptional speed. Furthermore, 

the feedback from the clinician allows 

the scientist to address clinically 

relevant questions and then adjust 

and test their hypotheses in a 

clinically relevant situation. The 

ability to conduct fundamental 

research-based clinical studies puts us 

in an excellent position to develop 

new therapies for the treatment of 

melanoma and other cancers. 

HSP90 and BRAF 

As part of our ongoing efforts 

in the basic research area, we have 

examined other approaches to 

target BRAF in melanoma and have 

discovered an exciting alternative 

approach. Another protein called 

HSP90 is responsible for the correct 

function of BRAF. When HSP90 

activity is blocked, BRAF cannot 

function and becomes destroyed by 

specialist machinery in the cell. 

We have shown that a drug called 

17-AAG, which blocks the function 

of HSP90, causes destruction of 

mutant BRAF. Importantly, we have 

shown that mutant BRAF is more 

sensitive to 17-AAG than normal 

BRAF, providing a therapeutic 

selectivity against the function 

of the mutant protein. 

17-AAG is currently being 

tested at the Royal Marsden 

and The Institute against 

melanoma and a range of 

other cancers. 

We are also combining our laboratory 

and clinical studies to test other 

compounds that may target BRAF 

in cancer. For example, the 

downstream target of BRAF in cells is 

a protein kinase called MEK (see 

article by Professor Martin Leach and 

Dr Nandita deSouza, p.34). We are 

currently exploring the potential of 

using compounds that target this 

kinase in the laboratory and the 

clinic. Finally, we are conducting a 

major programme to develop new 

agents that directly target BRAF. The 

specific aim is to develop drugs 

that will enable us to treat melanoma 

patients by directly targeting mutant 

BRAF. These drugs may also prove 

useful for other cancers that rely on 

mutant BRAF, such as colorectal 

and thyroid cancer. This work, being 

conducted at The Institute of Cancer 

Research, is a collaboration between 

The Institute, the Wellcome Trust 

and Cancer Research UK. 

Laboratory and clinical 

collaboration: The future 

The importance of the link between 

the research laboratory and the clinic 

cannot be over-emphasised. The 

constant dialogue between these two 

settings allows us to translate our 

50

CANCER RADIOTHERAPY THERAPEUTICS/ – PROSTATE CANCER CANCER BIOLOGY 

ACTIVE SURVEILLANCE APPROACH 

TO PROSTATE CANCER 

The aggressiveness of prostate cancer varies considerably. 

Active surveillance aims to minimise unnecessary treatment and 

help define the factors that contribute to disease outcome. 

Chris Parker 

MD MRCP FRCR 

Chris Parker is a Cancer 

Research UK Clinician Scientist 

in the Section of Academic 

Radiotherapy at The Institute of 

Cancer Research and Honorary 

Consultant in the Department 

of Radiotherapy at The Royal 

Marsden NHS Foundation Trust 

Prostate cancer: 

Occurrence and risk 

• Prostate cancer is the most common 

cancer in UK men, with 30,000 new 

cases diagnosed each year. 

• As many as 80% of men develop 

prostate cancer during their 

lifetime, but in most cases it does 

not cause any ill health. Around 

6% of men experience symptoms of 

the disease, while 3% of men die 

of prostate cancer. 

• Screening for prostate cancer 

using the Prostate Specific 

Antigen (PSA) blood test remains 

very controversial but, for 

better or worse, PSA testing of 

healthy men is increasing. 

• The first randomised trial 

comparing surgery versus watchful 

waiting in men with prostate 

cancer, reported in 2005, showed 

a 5% survival advantage for 

surgery but with a 28% risk of 

urinary incontinence and 

a 35% risk of impotence. 

Active surveillance of early 

prostate cancer 

Most prostate cancers will never 

cause any problems and do not need 

any treatment. On the other hand, 

some prostate cancers will grow and 

spread, and become life threatening. 

Unfortunately, it can be difficult to 

distinguish between these two 

types of the disease. One solution is 

to treat all cases, ‘to be on the safe 

side’. However, while curative 

treatment for prostate cancer may 

or may not improve a man’s 

longevity, it can certainly have a 

big impact on his lifestyle with 

side-effects including impotence and 

incontinence. Ideally, treatment 

should be restricted to those who 

need it. Active surveillance aims 

to individualise the management of 

early prostate cancer by selecting 

only those men with significant 

cancers for curative treatment. 

Patients on active surveillance 

are closely monitored using 

PSA blood tests and repeat 

prostate biopsies. The choice 

between continued observation 

and curative treatment is 

based on evidence of disease 

progression during this 

monitoring. 

Studies at the Royal Marsden 

In 2002, we began a prospective 

study of active surveillance of 

prostate cancer at the Royal Marsden. 

This initiative, funded by the 

National Cancer Research Institute 

Southern Prostate Cancer 

Collaborative, has grown to become 

the largest study of its kind and 

has already recruited over 300 men 

with prostate cancer. Currently, 

51


Figure 1. Diffusion-weighted magnetic resonance imaging (DW-MRI) provides image contrast through measurement of the diffusion properties 

of water within tissues. The white arrow indicates an area of abnormal water diffusion within the prostate gland. It is possible that DW-MRI 

may provide a better indication of prostate cancer behaviour than conventional MRI techniques. 

around 20% of these men have 

received curative treatment, while 

the rest have continued on 

observation. None of these patients 

have developed any symptoms from 

prostate cancer, or any spread of the 

disease, and none have died of 

prostate cancer. These preliminary 

results are most encouraging and 

have established the feasibility of 

active surveillance for men with 

localised prostate cancer. 

The initial findings from the 

Marsden active surveillance study 

suggest that the size of a man’s 

prostate gland may be more 

important than had previously been 

appreciated. As men get older, their 

prostate gland enlarges but the degree 

of enlargement can vary as much 

as 10-fold between individuals. We 

found that the ratio of the PSA 

level in the blood to the size of the 

prostate gland, which is known 

as the ‘PSA density’, is an important 

predictor of disease progression in 

men with prostate cancer undergoing 

active surveillance. If this finding 

were to be confirmed, it would 

provide one very simple way of 

helping to individualise treatment for 

men with localised prostate cancer. 

Those with a small prostate might be 

better suited to immediate curative 

treatment, while observation may be 

more appropriate for those with 

a larger prostate. However, there will 

always be exceptions to this general 

rule, and it remains vital to identify 

better predictors of individual 

prostate cancer behaviour. 

At present, repeat prostate biopsy is 

the gold standard method to identify 

tumour progression, and hence the 

need for treatment, in men on active 

surveillance. Prostate biopsy can 

be uncomfortable for patients, and 

also carries risks of bleeding and 

infection. In collaboration with Dr 

Nandita deSouza (Cancer Research 

UK Clinical Magnetic Resonance 

Research Group at The Institute), we 

are evaluating novel magnetic 

resonance techniques in men on 

active surveillance to see whether 

they can provide a non-invasive 

indicator of tumour progression 

(see article by Professor Martin Leach 

and Dr Nandita deSouza, p.34). 

Another trial (designated Prostate 

START) is due to open at the Royal 

Marsden during 2006. Prostate START 

is an international, multicentre study 

that will compare active surveillance 

against standard curative treatment 

for prostate cancer in 2,000 men. The 

main endpoint of the trial, to be coordinated 

at The Institute's Clinical 

Trials Unit (UK Principal Investigator: 

Cr Chris Parker), is long-term survival. 

It is hoped that active 

surveillance will avoid 

‘unnecessary’ treatment, 

and its associated sideeffects, 

without detriment 

to long-term survival. 

Psychological impacts of 

active surveillance 

One concern about active surveillance 

is that men may find it difficult to 

deal with the knowledge that they 

have a cancer that is not being 

treated. Dr Maggie Watson and Miss 

Katrina Burnet, from the Psychology 

Research Group at The Institute, 

are evaluating the prevalence 

of anxiety and depression in men 

on active surveillance, in order 

to better understand the underlying 

52


psychological factors. Their initial 

findings are reassuring. It appears 

that men on active surveillance 

for prostate cancer are no more 

anxious than those receiving 

active treatment, or indeed than 

UK cancer doctors! 

enables many candidate biomarkers 

to be evaluated rapidly and makes 

highly efficient use of the small 

amounts of prostate tissue available. 

Dr Jhavar is now studying biopsies 

from the active surveillance patients 

in this way in order to identify which 

pattern of markers best predicts 

prostate cancer behaviour. 

surgically excised. Several nutritional 

factors have been implicated in the 

development and progression of 

prostate cancer. For example, initial 

studies have suggested that 

supplements containing selenium, 

vitamin E or vitamin D may reduce 

the risk of the disease. 

Active surveillance provides 

an excellent opportunity for 

research to identify markers 

of prostate cancer behaviour. 

Markers of prostate 

cancer behaviour 

Men taking part in the Royal Marsden 

study have given samples of blood, 

urine and prostate tissue for research. 

These samples are uniquely valuable 

because, unlike samples in any other 

prostate tissue bank, they are linked 

to information on the natural history 

of each individual cancer. They are 

now being used in a range of 

studies, both within The Institute of 

Cancer Research and elsewhere, to 

evaluate prostate cancer biomarkers. 

For example, Dr Sameer Jhavar, 

working in Professor Colin Cooper’s 

laboratory at The Institute, has 

devised a new technique that allows 

prostate biopsy tissue to be used 

to make microarrays. This technique 

Accurate prediction of 

individual prostate cancer 

behaviour will be invaluable 

in helping to decide 

which men need treatment 

and which do not. 

The future of active 

surveillance 

In the future, active surveillance 

could be the setting for trials to test 

low-toxicity interventions designed 

not to eradicate the disease but 

rather to alter its natural history. At 

present, using regular PSA testing 

in healthy men, it is possible to 

diagnose prostate cancer 10-15 years 

before it would cause any symptoms. 

A well-tolerated intervention that 

slowed the rate of progression still 

further could turn prostate cancer 

into a chronic condition to be 

controlled, rather than a disease to be 

We plan to study the effect 

of nutritional supplements on 

the rate of disease progression 

in men with localised prostate 

cancer on active surveillance. 

In summary, active surveillance is an 

attractive and increasingly popular 

approach to the management of early 

prostate cancer. It is also an ideal 

setting for research to identify new 

markers of prostate cancer behaviour. 

Such markers could transform our 

ability to target treatment to those 

who need it. A long-term hope is 

that nutritional intervention studies 

in men on active surveillance could 

lead to a whole new way of managing 

prostate cancer, aimed at disease 

control rather than cure. This would 

be a major step forward because 

it would avoid the burden of adverse 

effects such as impotence that 

are associated with conventional 

surgical treatment. 

A B C D 

Figure 2. Prostate 

needle biopsies (A) 

are usually sectioned 

longitudinally. 

In order to create biopsy tissue microarrays, the biopsies are cut into multiple 

chequers (B) and embedded in a new paraffin block (C). 

They can then be sectioned 

transversely (D), enabling 

multiple tissue markers to 

be assessed in each case. 

53

HEALTH RESEARCH - CANCER CARE 

THE SEPSIS SYNDROME 

In order to understand the challenges of diagnosis, and the lack 

of progress in reducing mortality rates, it is important to understand 

the basic mechanisms and pathophysiology of the sepsis syndrome. 

Shelley Dolan 

RGN MSc 

Shelley Dolan is Nurse 

Consultant Cancer: Critical Care 

and Head of Nursing Research at 

The Royal Marsden NHS 


Sepsis susceptibility 

Sepsis is a leading cause of death 

across the world and the commonest 

cause of death in non-coronary 

intensive care units worldwide. The 

documented incidence of sepsis cases 

per annum worldwide is 1.8 million 

but there are considerable problems 

with diagnosis and monitoring 

in many countries, and this figure 

is therefore likely to be an underestimation. 

In fact it is likely that 

the number of cases per annum 

may reach 18 million corresponding 

to an incidence of 3 in 1000. The 

mortality rate is generally between 

30-70% though it can be higher in 

a person with a pre-existing disease. 

As the older population is 

increasing, and the elderly are both 

more susceptible to sepsis and 

have a higher associated mortality, 

it is predicted that incidence 

and mortality will continue to grow. 

Other influences on incidence are 

likely to be factors such as the increase 

in nosocomial infections and higher 

rates of antimicrobial resistance. 

Pathophysiology of the 

sepsis syndrome 

The sepsis syndrome is a complex 

systemic inflammatory condition 

associated with infection. It is 

not the infective pathogen that 

directly causes the sepsis syndrome 

and corresponding high mortality 

associated with severe sepsis but 

the host response to that pathogen. To 

appreciate the current understanding 

of the syndrome it is useful to divide 

the complicated pathophysiology into 

four main areas: 

• The individual host response 

• The role of the endothelium 

(lining of blood vessel) 

• The disequilibrium of the 

pro-inflammatory and antiinflammatory 

mechanisms 

• Activation of the coagulation 

pathways 

Following invasion of bacteria, local 

endothelial cells cause the release 

of inflammatory mediators and the 

activation of the clotting cascade. 

This endothelial action is a part of 

the normal healthy response of 

the body to an invading pathogen. 

In severe sepsis, however, the 

endothelial response is no longer a 

healthy response but a dysfunctional 

one where, rather than local 

measured activity, there is an 

excessive, sustained and generalised 

activation of the endothelium. 

This generalised host response can 

no longer be regulated by local 

negative feedback mechanisms and 

results in a severe disequilibrium 

of inflammatory response, which 

causes generalised tissue injury, 

vascular permeability, shock and 

multi-organ failure. 

54


Table 1. The risks of infection and sepsis for cancer patients 

Characteristic 

Reason for greater risk of sepsis 

Repeated hospitalisation 

Increase in nosocomial (hospital-acquired) infections 

Repeated invasive therapy utilising shortor 

long-term central venous access devices (CVAD) 

Increased exposure to CVAD-associated infections 

Bone marrow suppression because of disease 

infiltration of the marrow (eg, in liquid cancers or 

metastatic disease involving the bone) 

Bone marrow suppression results in pancytopaenia 

with a resultant lowering of white cell count, platelet 

count and red cell count. The white cells are the 

body’s first and most important response to infection 

Bone marrow suppression as a result of treatment 

(chemo/radiotherapy) 

The resultant neutropenia (reduction in the 

absolute neutrophil count) renders the body exquisitely 

susceptible to infections 

Malnutrition associated with disease or treatment 

Poor immunity and resistance to infection 

A predominantly older population who are more likely 

to have co-morbid conditions 

Generally frail health means more likely to be 

less resistant to infections 

Increased exposure to transfused blood and its 

components either as a result of repeated surgery 

or the disease and chemo/radiotherapy 

The transfusion of donated blood and its components, 

such as platelets, clotting factors and fibrinogen, 

carries the risk of transmitting donor infections 

There is a heterogeneity of 

response depending on several 

individual host factors such 

as age, genetics, any pre-existing 

disease, gender, the type of 

pathogen and the area of the 

body most affected. 

Sepsis and cancer 

All cancer patients are very 

susceptible to sepsis and its associated 

symptoms for many reasons (see 

Table 1). Patients suffering from types 

of cancer where the bone marrow 

is diseased, such as leukaemia, 

lymphoma and myeloma, are more 

vulnerable to sepsis as these cancers 

directly affect the body’s immune 

response. The definitive treatment for 

these ‘liquid cancers’ is marrow 

ablative chemotherapy which is 

where a patient’s bone marrow 

is destroyed before replacing it with 

allogeneic (from another person) 

or autologous (from self) stem cells 

or bone marrow. There are also 

some cancer patients with solid 

tumours (eg, teratoma) who 

may need to receive the same 

marrow ablative chemotherapy. 

The mortality rate for cancer 

patients who develop sepsis and 

then severe sepsis is quoted as 

being 65 to 85%, and is the 

major reason for bone marrow 

transplant-associated deaths in 

the first six weeks of therapy. 

Diagnosis of sepsis 

The early diagnosis of patients with 

sepsis has been shown to reduce 

mortality rates. It allows prompt 

treatment with antibiotics and also, 

where possible, for the removal of the 

sepsis source. For example, surgical 

intervention to remove a portion of 

gangrenous gut, or the removal of a 

skin tunnelled catheter in people with 

cancer, can be performed. 

The difficulty for all nurses and 

healthcare teams is that the early 

indications may be subtle and 

difficult to recognise. It is also 

the case that some of the clinical, 

biochemical and haematological 

signs of sepsis are also indicators 

of non-sepsis conditions such as 

pancreatitis, cerebral haemorrhage 

or other major shock conditions. 

Much work over the last 10 years 

has been concentrated on the early 

recognition and subsequent early 

therapy for sepsis in an attempt to 

prevent the systemic symptoms of 

generalised inflammatory change, 

tissue damage, increased cell 

permeability, shock and organ damage. 

55


If we can identify patients early 

and monitor them closely, we may 

be able to prevent critical illness and 

reduce the high sepsis mortality rates 

especially in people with cancer. 

As nurses work so intimately with 

people who are at the highest 

risk of developing sepsis, they 

are key members of the 

multidisciplinary team. 

A study has been designed 

to help nurses to identify at-risk 

patients, and patients who are 

deteriorating rapidly. The study 

aims to increase knowledge 

of the sepsis syndrome, translate 

that knowledge into action, 

and reduce the vulnerability 

of the person with cancer. 

Early diagnosis of 

sepsis study 

There are several subtle early 

indicators of sepsis in a patient that 

the nurses in this study will explore. 

There are also a range of indicators in 

the patient’s blood such as a rise in 

white blood cells, a rise in C-reactive 

protein (CRP) and several other 

inflammatory markers that can be 

measured in the laboratory. 

The overall aims of the study are to: 

• Improve the awareness of the 

sepsis syndrome across The Royal 

Marsden NHS Foundation Trust and 

the imperative for early diagnosis 

• Strengthen the clinical 

assessment package 

• Decrease any delay in treating 

the patient 

• Determine the feasibility of using 

a bedside blood test, PCT-Q, as part 

of the clinical assessment package. 

The key interventions that are being 

tested in this prospective trial are: 

a) dedicated ward teaching sessions 

to 200 nurses across the Trust on 

the sepsis syndrome, and its early 

diagnosis and treatment; and b) 

the feasibility of ward-based nurses 

using a bedside test (PCT-Q) which 

measures the level of the marker 

procalcitonin (PCT). 

PCT-Q is an easy to use blood testing 

kit (see Figure 1) that measures the 

level of procalcitonin in the blood 

within 30 minutes and gives a semiquantifiable 

index of the severity 

of the sepsis. Procalcitonin, the prohormone 

of calcitonin, was first 

discovered in 1961 and shown to be 

involved in lowering serum calcium. 

However, following a meningitis 

outbreak and a case of staphylococcal 

toxic shock syndrome in 1983, its role 

in sepsis has been studied. In over 

1,200 studies conducted from the 

1990s to the present, procalcitonin 

has been shown to be a more reliable 

and specific early indicator of sepsis 

than other indicators such as CRP. 

56 

Figure 1. The easy to use PCT-Q kit.


300 

Maximal increase 

50.6 ng/ml x h 

250 

200 

PCT (ng/ml) 

150 

100 

50 

Induction phase 

0.5 ng/ml x h 

0 

2 4 6 8 10 12 14 16 18 20 22 24 

Figure 2. Rapid rise in procalcitonin as a response to infection and developing sepsis. 

Time (h) 

Procalcitonin rapidly rises as a 

response to sepsis and then stays 

high in the blood for 24-48 hours 

(see Figure 2). 

In 2003 a bedside test called 

PCT-Q became available 

allowing the rapid measurement 

of procalcitonin, a marker for 

sepsis. 

Although PCT-Q has been used 

previously in small populations, 

this is the first time it will have 

been used in a large sample (570 

patient episodes) and by ward-based 

nurses. Nurse and patient accrual 

is now complete and the data 

are being analysed. 

Early analysis of the study 

has revealed that correlations 

between PCT levels and 

the onset of sepsis and severe 

sepsis are highly statistically 

significant. In over 500 episodes 

of neutropenic and nonneutropenic 

sepsis, PCT levels 

were more accurate in predicting 

sepsis than those of CRP. 

Qualitative data analysis from 

interviews with the nurse participants 

revealed some valuable data regarding 

early detection of sepsis in cancer 

patients. Nurses who have regular 

contact with their patients are able 

to recognise subtle changes in 

demeanour, behaviour or appearance. 

This is a prompt for further 

examination and leads to discovery 

of changes in the patient’s vital signs 

or blood tests that may indicate sepsis. 

The conclusions of this study 

indicate that it is not only skilled 

nursing but also, crucially, its 

continuity which are important 

to the early detection and 

treatment of sepsis. 

57

RADIOTHERAPY – TAILORED TREATMENT 

DOSIMETRY FOR TARGETED 

RADIONUCLIDE THERAPY 

Combined advances in molecular imaging and radionuclide therapy 

have major implications in the move towards tailored cancer treatment. 

Glenn Flux 

PhD 

Glenn Flux is Leader of the 

Radioisotope Physics Team in the 

Joint Department of Physics at 


and The Royal Marsden NHS 


Introduction to targeted 

radionuclide therapy 

Targeted radionuclide therapy (TRT) 

kills cancer cells by delivering a lethal 

dose of radiation. The radiation 

is usually attached to a ‘carrier’ that 

selectively seeks out tumour cells. 

As with external beam radiotherapy, 

TRT offers the advantage of 

delivering high radiation doses to 

a specific target but in common 

with chemotherapy it can deliver 

treatment systemically, attacking 

multiple sites throughout the body. 

It is a relatively benign treatment 

that does not incur the side-effects, 

such as hair loss and prolonged 

nausea, often seen in more 

conventional treatments. 

How radiation works for 

cancer management 

When a radioactive atom decays, 

one or more of a number of particles 

are emitted. Beta particles act 

like small billiard balls, travelling 

only short distances in the body 

until hitting nearby cells and killing 

or damaging them. It is these 

particles that are mainly responsible 

for delivering radionuclide treatment. 

Since the radioactivity is constantly 

1 

6 

5 2 

3 

4 

Figure 1. The use of radiation for cancer treatment in TRT: 

A radioactive atom decays (1) and emits both 

gamma rays (2) and beta particles (5). 

The gamma rays are imaged by a scintillation 

camera (3) to produce functional images (4). 

The beta particles hit nearby cells (6), 

damaging or killing them. 

58


decaying, the success of a treatment 

is dependent on the amount of 

radioactivity that is taken up in a 

tumour and how long it remains 

localised. With many radioisotopes 

used in TRT, gamma rays are also 

emitted. These rays are simply high 

energy light that is invisible to 

the naked eye but imageable by the 

specially designed scintillation 

cameras which are used in nuclear 

medicine. It is therefore possible to 

simultaneously administer treatment 

and to see the radiation that delivers 

the treatment in vivo (see Figure 1). 

Dosimetry for patientspecific 

treatment planning 

Until recently, TRT has been 

delivered either with fixed levels of 

activity or, more rarely, according 

to the patient’s weight. The increasing 

use of molecular imaging is 

changing the basic approach to 

treatment planning for TRT 

since it is now possible to take into 

account the patient’s specific 

biokinetics to determine how their 

treatment could be tailored. Images 

obtained after administration can 

be used to monitor where the 

radiation is taken up within a patient. 

It has been shown that if two 

patients are given the same amount 

of radioactivity, there can be a 

substantial variation in the quantity 

of radiation that is taken up in 

a tumour or in a normal organ, and 

in the time that the radiation 

remains there. 

Our research is focused 

on measuring radiation 

‘uptake and retention’ 

characteristics of tumours 

and normal organs, with 

the aim of tailoring treatment 

to individual patients. 

For example, where a patient has 

relatively little radioactivity taken 

up in tumour tissue, or if they lose 

the radioactivity quickly, higher 

activities can be safely administered 

to ensure that the patient receives 

the prescribed radiation absorbed 

dose. The measurement techniques 

are also applied to normal organs 

that could be adversely affected, 

such as the bone marrow, liver or 

kidneys, to ensure that these do 

not receive too high an absorbed 

dose. The practice of studying 

the distribution of radiation in 

individual patients in this way 

is termed ‘dosimetry’. 

TRT: 

A multidisciplinary approach 

Whilst the use of relatively small 

quantities of radiopharmaceuticals 

for diagnostic imaging has been 

a mainstay of cancer management 

for many decades, TRT has remained 

a little-used method of cancer 

treatment, in part because of 

its complexity and the need for 

a multidisciplinary approach. 

To successfully apply patient-specific 

treatment it is necessary to have 

a team comprising clinical and 

medical oncologists, nuclear 

medicine physicians, specialist nurses, 

radiographers and physicists. 

Together the Royal Marsden and The 

Institute form one of only a very 

few cancer centres in Europe that are 

able to do this. Advances are being 

made in this field supported by grants 

from a number of funding bodies, 

including the Neuroblastoma Society, 

Cancer Research UK and the 

European Union. New methods 

devised to calculate uptake and 

retention characteristics from the 

images have been made possible 

by the increase in computing power 

over recent years and we enjoy close 

collaborations between specialist 

centres in Europe and the US. 

Translational research 

The Radioisotope Physics Team in 

the Joint Department of Physics 

comprises both research and clinical 

scientists. Basic research is being 

conducted into problems such as 

computer and mathematical 

modelling of the scintillation cameras 

(SPECT and PET/CT) and of the 

interactions of radiation in tissue, 

with results that may be subsequently 

applied to a range of imaging studies 

or treatments. Recently, the optimal 

method for bremstrahlung imaging of 

pure beta emitting radionuclides such 

as 32-Phosphorus and 90-Yttrium has 

been determined, and modelling 

studies have been conducted to see 

whether calculated radiation doses 

can be translated directly into 

survival probabilities for cancer or 

normal cells. 

One major problem to overcome in 

dosimetry for TRT is that at present 

there are no internationally accepted 

standard methods to calculate 

radiation doses. To address this, an 

extensive study of error propagation 

is being carried out to determine 

the uncertainties inherent in the 

various methods of dosimetry 

that are used in different centres, 

and radiation-sensitive polymer 

gels are being used to verify dosimetry 

techniques. This will facilitate 

multi-centre trials whereby results 

obtained at different centres 

may be directly compared. 

In conjunction with 

basic research, this new 

methodology is being 

applied to a range of clinical 

treatments with established 

and newly developed 

radiopharmaceuticals. 

59


131-Iodine mIBG for 

neuroblastoma (with Dr Frank 

Saran, Dr Donna Lancaster, 

Professor Andy Pearson) 

Neuroblastoma is a childhood cancer 

of neural crest cells. In 50% of cases 

it has metastasised by the time of 

diagnosis with a 5-year survival 

rate of only 30-40%. 

In conjunction with 

University College Hospital, 

we are leading a new European 

study to use 131-Iodine mIBG 

to treat patients that have 

relapsed after chemotherapy 

treatment. mIBG is a 

noradrenaline analogue 

that specifically targets 

neuroendocrine cells. 

In this study, the first of its kind, 

the quantity of radiation given is 

calculated based on the patient’s 

individual whole-body uptake and 

retention. Activity is administered 

in two fractions, spaced two weeks 

apart, with the aim of delivering 

a total whole-body absorbed dose of 

4 Gy. The activity for the first 

fraction is calculated from a weightbased 

formula whilst the activity 

for the second is calculated from 

measurements obtained from the 

first treatment so that a higher or 

lower activity is given as required. 

To date, the total activities 

administered have been within 10% 

of the target, ensuring that patients 

therefore receive a similar treatment. 

In some cases this has resulted in 

administered activities that are up to 

4 times higher than those routinely 

given, and initial evidence indicates 

that the increased administration 

results in higher tumour doses. 

This procedure has already yielded 

promising results (see Figure 2). 

186-Rhenium HEDP for bone 

metastases from prostate cancer 

(with Professor David 

Dearnaley, Dr Val Lewington) 

A study has recently been completed 

to calculate radiation doses from 

high activity treatment of bone 

metastases from prostate cancer. We 

have formulated a method to 

successfully predict patient-specific 

whole-body absorbed doses that 

would be delivered to a patient in 

advance of the treatment, based 

on routine clinical measurements 

such as kidney function and levels 

of alkaline phosphatase. A new 

study will target bone metastases 

with 223-Radium. 

Bone marrow 

metastases 

Normal 

uptake 

Figure 2a. This 6 year old child with neuroblastoma suffered 

relapse from previous chemotherapy treatment and was treated 

with 131-Iodine mIBG following the Royal Marsden protocol to 

administer a dose based on the child’s own whole-body dosimetry 

measurements. This gamma camera scan taken before treatment 

clearly shows metastases in the bone marrow. 

Figure 2b. The child was kept in isolation for several days, although 

she was attended by nurses and family. She suffered no sickness or 

hair loss. Three months later, a repeat scan showed that the bone 

marrow metastases had cleared. 

(Images courtesy of Dr Alexander Becherer, Department of Nuclear 

Medicine, University of Vienna, Medical School, Vienna, Austria) 

60


Figure 3. 

(Left) A transaxial slice 

showing radiotherapy to a 

tumour situated near the 

spine. The treatment is limited 

by adjacent tissue, including 

the spinal chord and the 

kidneys (outlined). 

Dose(Gy) 60 

Dose(Gy) 40 

(Right) The same slice with 

treatment delivered from TRT. 

In this case, the red marrow 

proves to be the dose-limiting 

organ. A combination of the 

two therapies can improve the 

therapeutic index. 

0 

0 

131-Iodine sodium iodide for 

thyroid cancer (with Dr Clive 

Harmer, Dr Masud Haq, Dr Chris 

Nutting, Dr Val Lewington) 

131-Iodine sodium iodide is the most 

established treatment using TRT and, 

in combination with surgery, has a 

relatively high response rate. Although 

patients are usually given standard 

quantities of radiation, some remain at 

high risk. A dosimetry-based approach 

to treatment for patients identified as 

high-risk has been started, and a 

further study is being conducted 

to determine the absorbed dose to 

salivary glands during treatment since 

salivary dysfunction is a common 

side-effect of high activity treatment. 

Adult neuroendocrine tumours 

(with Dr Val Lewington, 

Dr Diana Tait) 

Dosimetry studies have 

determined that radiation doses 

delivered to tumours from standard 

administrations can range from 10 Gy 

to 120 Gy. As with neuroblastoma, 

adult neuroendocrine tumours have 

been treated here with 131-Iodine 

mIBG according to patient-specific 

whole-body uptake measurements, 

thereby maximising administered 

activities whilst keeping doses to 

normal organs such as the liver to a 

safe level. A promising treatment now 

underway targets cell surface 

neuroreceptors found in 90% of these 

tumours with neuropeptides 

radiolabelled with 90-Yttrium. 

32-Phosphorus for 

craniopharyngioma 

(with Dr Frank Saran) 

Craniopharyngioma is a disease 

often seen in paediatrics that results 

in the formation of large cysts in the 

brain. We are commencing a new 

study to use image-based dosimetry 

to direct the use of 32-Phosphorus 

injected directly into the cyst. 

Treatment is planned from initial 

scans acquired with a tracer quantity 

of 99m-Technetium to determine the 

quantity of radiation to inject. 

The future 

TRT is increasing rapidly in 

terms of the numbers of patients 

and the range of cancers treated. 

Individualised image-based treatment 

promises dramatic benefits. As the 

potential of dosimetry-based TRT is 

realised it is likely that this treatment 

will be more commonly used at 

an earlier stage in the patient’s 

treatment, rather than in later stage 

patients as is currently often the case, 

and that it will be increasingly used 

in conjunction with chemotherapy 

and radiotherapy to provide 

synergistic treatment. For example, 

in one project carried out in 

collaboration with Dr Phil Evans 

(Radiotherapy Physics Research Team 

at The Institute), it was shown that 

external beam radiotherapy could be 

planned taking into account the 

absorbed dose distribution delivered 

from the TRT. The advantage of this 

approach would be that whilst both 

types of radiotherapy treat the same 

volume, each has a different doselimiting 

factor: the absorbed dose to 

the adjacent tissue in the case 

of external beam radiotherapy; and 

frequently the red marrow in the 

case of TRT (see Figure 3). In tandem 

with the developments in TRT, 

there is an increasing interest in 

molecular imaging, particularly 

with PET/CT that enables the study 

of biological processes at the 

cellular and molecular level. 

These imaging techniques are 

being increasingly used to examine 

the pharmacokinetics and 

pharmacodynamics of new drugs. 

An exciting area of research that 

could now be developed is to adapt 

methods for quantitative imaging and 

dosimetry and apply them to other 

drugs which can be radiolabelled. 

Image quantification 

and dosimetry will aid 

interpretation and 

understanding of the images 

acquired from new drugs 

or radiopharmaceuticals and, 

by administering them 

on a patient-specific basis, 

will help to fully realise 

their potential efficacy. 

61



The Institute and Royal Marsden on the Internet 

The Internet has revolutionised the way people access information. Over the past year, 

both The Institute and the Royal Marsden websites have been completely redesigned and 

modernised to reflect our image as a joint world class cancer centre. 

The review articles in this 

report describe only a handful 

of our research developments. 

Further research achievements 

and research projects currently 

underway can be explored 

on The Institute and the Royal 

Marsden websites: 

http://www.icr.ac.uk/ 

researchsections 

http://www.royalmarsden.nhs. 

uk/rmh/healthcare/research/ 

researchoverview 

Royal Marsden website 

The new Royal Marsden website 

is a valuable and powerful 

communication tool for patients, 

healthcare professionals, staff and 

members of the public. It is vital 

for providing patients with 

information about what to expect 

when receiving treatment at the 

Royal Marsden and information 

about different types of cancer and 

treatments. Healthcare professionals 

can browse information on patient 

referrals, training and educational 

opportunities, research projects 

being undertaken at the hospital, 

and apply for jobs. 

The new site includes a redesigned 

structure, where every page has clear 

links to the five main areas of the site. 

With an improved search facility, 

information is easier to find and 

a new content management system 

allows authors from around the 

Trust to create and maintain web 

content, keeping the site up to date. 

The Institute of Cancer 

Research website 

The new fully interactive Institute 

website showcases scientific advances 

and raises awareness of our worldclass 

research, while encouraging 

fundraising involvement and 

donations. As a research organisation, 

a Higher Education Institution and 

a charity, The Institute’s website has 

a number of key audiences. 

The new site clearly and effectively 

addresses the needs of these groups 

which include the international 

research community, potential staff, 

people affected by cancer, medical 

practitioners, students and 

charity supporters. 

The redesigned site also 

has a comprehensive categorised 

search function, a fully searchable 

publications database and an 

online application function for 

PhD studentships. The site is hosted 

within a new intuitive content 

management system, allowing our 

researchers and corporate support 

staff to easily update content ensuring 

that our achievements are available 

in the public domain as soon 

as possible. 

62


Research publications 

During 2005, Institute and Royal 

Marsden scientists published over 

500 primary research articles in 

peer-reviewed journals, such as the 

New England Journal of Medicine, 

Nature and the Lancet, to name 

just a few. 

Many of our world-class researchers 

were also invited to contribute 

review articles to some of the most 

prestigious journals in their fields. 

More than 60 review articles were 

published, including articles in Cancer 

Cell, Lancet Oncology and 

the Journal of Clinical Oncology. 

A full listing of all our research 

publications for 2005 and other years 

is available through the online 

Research Publications Database, at: 

http://miref.icr.ac.uk/ 

63

RESEARCH DEPARTMENTS 


Our Research Centres, Departments, Sections and Units 

Our research is carried out across 34 centres, departments, sections and units, 

many of which are joint divisions between The Institute and the Royal Marsden. 

Our research is categorised into seven broad research themes. The departments 

associated with each of these themes are shown below. 

Cancer Biology 

The Breakthrough Toby 

Robins Breast Cancer 

Research Centre 

DIRECTOR: Professor A Ashworth 

Section of Cell and Molecular 

Biology and Cancer Research 

UK Centre for Cell and 

Molecular Biology 

CHAIRMAN AND CENTRE DIRECTOR: 

Professor C J Marshall 

Section of Gene Function and 

Regulation 

ACTING CHAIRMAN: 

Professor P W J Rigby 

Section of Haemato-Oncology 

CHAIRMAN: Professor M F Greaves 

Section of Structural Biology 

CO-CHAIRMEN: Professor L H Pearl, 

Professor D Barford 

Cancer 

Genetics 

Section of Cancer Genetics 

CHAIRMAN: Professor M R Stratton 

Section of Paediatric 

Oncology, Cancer Research 

UK Academic Unit of 

Paediatric Oncology, and the 

Children’s Cancer Unit 

CHAIRMAN AND HEAD OF CLINICAL 

UNIT: Professor A D J Pearson 

Cancer 

Therapeutics 


Biochemistry 

HEAD OF DEPARTMENT: 

Professor M Dowsett 

Breast Unit 

in association with the Section 

of Medicine 

HEAD OF UNIT: Professor I E Smith 

Cancer Research UK Centre 

for Cancer Therapeutics, 

Section of Cancer 

Therapeutics and Clinical 

Pharmacology Unit 

CENTRE DIRECTOR AND SECTION 

CHAIRMAN: Professor P Workman 

Section of Clinical Trials 

CHAIRMAN: Professor J M Bliss 

Gastrointestinal Cancer Unit 


of Medicine 

HEAD OF UNIT: 

Professor D Cunningham 

Gynaecology Unit 


of Medicine 

HEAD OF UNIT: Professor S B Kaye 



Haemato-Oncology Unit 

HEAD OF UNIT: Professor G J Morgan 

Lung Cancer Unit 


of Medicine 

HEAD OF UNIT: Dr M E R O’Brien 

Section of Medicine, 

including the Cancer 

Research UK Department of 

Medical Oncology 

CHAIRMAN AND HEAD OF 

DEPARTMENT: Professor S B Kaye 








64

Sarcoma Unit 


of Medicine 

HEAD OF UNIT: Professor I R Judson 

Skin and Melanoma Unit 


of Medicine 

HEAD OF UNIT: Professor M E Gore 

Molecular 

Pathology 



Section of Molecular 

Carcinogenesis 

CHAIRMAN: Professor C S Cooper 








Imaging 

Research 

& Cancer 

Diagnosis 

Anatomical Pathology 

Department 


Mr A C Wotherspoon 

Academic and Service 

Departments of Diagnostic 

Radiology 

HEADS OF DEPARTMENTS: 

Professor J E S Husband (Sutton), 

Dr D M King (Chelsea) 


Cancer Research UK 

Clinical Magnetic Resonance 

Research Group 

JOINT DIRECTORS: 

Professor M O Leach, Dr N deSouza 

Department of Nuclear 

Medicine 

CONSULTANT: Dr G J R Cook 

Joint Department of Physics 


Professor S Webb 

Radiotherapy 

Head and Neck Cancer Unit 

HEAD OF UNIT: Dr C M Nutting 

Neuro-Oncological 

Cancer Unit 

HEAD OF UNIT: Dr F Saran 

Joint Department of Physics 


Professor S Webb 

Section of Academic 

Radiotherapy and 

Department of Radiotherapy 

SECTION CHAIRMAN: 

Professor A Horwich 

DEPARTMENT HEAD: Dr P R Blake 

Thyroid and Isotope 

Treatment Unit 

HEAD OF UNIT: Dr C M Nutting 

HEAD OF ISOTOPE UNIT: 

Dr V J Lewington 

Urology and Testicular 

Cancer Unit 

HEAD OF UNIT: 

Professor D P Dearnaley 

Health 

Research 

Section of Epidemiology, 

including the Department of 

Health Cancer Screening 

Evaluation Unit 

CHAIRMAN: Professor A J Swerdlow 


UK Epidemiology and 

Genetics Unit 

CHAIRMAN: Professor J Peto 

Directorate of Nursing, 

Rehabilitation and 

Quality Assurance 

CHIEF NURSE/DEPUTY CHIEF 

EXECUTIVE: 

Professor D Weir-Hughes 

Department of Pain and 

Palliative Medicine 

HEAD OF SERVICES: Dr J Riley 

Psychological and Pastoral 

Care and Psychology 

Research Group 

HEAD OF SERVICES: Dr M Watson 

List reflects the status as at April 2006. 

65

SENIOR STAFF AND COMMITTEES 2005 

SENIOR STAFF 

AND COMMITTEES 2005 


BOARD OF TRUSTEES 

Lord Faringdon (Chairman) 

(to September 2005) 

Lord Ryder of Wensum OBE (Chairman) 

(from October 2005) 

Dr J M Ashworth MA PhD DSc 

(Deputy Chairman) 

Mr E A C Cottrell (Honorary Treasurer) 

Professor P W J Rigby PhD FMedSci (Chief 

Executive) 

Professor R J Ott PhD FInstP CPhys 

(Academic Dean) (to September 2005) 

Professor A Horwich 

PhD FRCP FRCR FMedSci (Academic Dean) 


Dr R Agarwal (to August 2005) 

Sir Henry Boyd-Carpenter KCVO MA 

Ms L Coutts (from October 2005) 

Dr S E Foden MA DPhil 

Mrs T M Green* MA (to March 2005) 

Mr R A Hambro 

Professor M O Leach PhD FInstP FIPEM 

CPhys FMedSci (to September 2005) 

Professor A Markham 

DSc FRCP FRCPath FMedSci 

Dr M J Morgan PhD 

Professor A van Oosterom MD PhD 

(from April 2005) 

Miss C A Palmer CBE MSc MHSM DipHSM 

Professor D Weir-Hughes OstJ MA EdD 

RN FRSH (Alternate Director) (to March 2005) 

Professor A D J Pearson MD FRCP 

FRCPCH (from October 2005) 

Professor D H Phillips PhD DSc FRCPath 

Miss A C Pillman OBE 

Mr R E Spurgeon 

Professor M Waterfield FRS FMedSci 

Miss M I Watson MA MBA FCIPD 

Professor S Webb PhD DIC DSc ARCS 

FinstP FIPEM FRSA CPhys CSci (from 

November 2005) 

Professor K R Willison PhD 


Mr J M Kipling FCA 

(Secretary of The Institute and Head of 

Corporate Services) 

Professor C J Marshall DPhil FRS 

FMedSci (Chairman of the Joint Research 

Committee) 

*Following revisions to The Institute’s Memorandum 

and Articles of Association approved by the 

Members of The Institute in March 2005 Mrs Tessa 

Green was appointed as The Royal Marsden’s 

Alternate Director with effect from April 2005 

CORPORATE 

MANAGEMENT GROUP 

Professor P W J Rigby PhD FMedSci 

(Chief Executive – Chairman) 

Mr J M Kipling FCA (Secretary of The 

Institute and Head of Corporate Services) 

Professor A Horwich PhD FRCP FRCR 

FMedSci (Director of Clinical Research 

and Development and Head of the Clinical 

Laboratories to September 2005; Academic 

Dean and Head of the Clinical Laboratories 

from October 2005) 

Professor C Isacke DPhil (from April 2005) 

Dr S R D Johnston PhD FRCP 

(Director of Clinical Research & Development) 

(from December 2005) 

Professor S B Kaye MD FRCP FRCR FRSE 

FMedSci 


(Academic Dean) (to September 2005) 


FMedSci (from October 2005) 

Professor N Rahman PhD FRCP (from 

October 2005) 


(Head of the Chester Beatty and Haddow 

Laboratories) (to March 2005) 

Professor P Workman PhD FIBiol FMedSci 

SECTION CHAIRMEN 

Chester Beatty Laboratories 

Professor A Ashworth PhD FMedSci 

(Director, The Breakthrough Toby Robins 

Breast Cancer Research Centre) 

Professor D Barford DPhil FMedSci 

(Section of Structural Biology to November 

2005) 

Professor M F Greaves PhD FRCPath 

Hon MRCP FRS FMedSci (Section of 

Haemato-Oncology) 


FMedSci (Section of Cell and Molecular 

Biology and Director, Cancer Research UK 

Centre for Cell and Molecular Biology) 

Professor L H Pearl PhD (Section of 

Structural Biology) (from November 2005) 


(Acting Chair of the Section of Gene Function 

and Regulation) 

Clinical Laboratories 

Professor J M Bliss FRSS (Section of 

Clinical Trials) 

Dr N deSouza MD MRCP FRCP FRCR 

(Co-Director, Cancer Research UK Clinical 

Magnetic Resonance Research Group) 

(from June 2005) 

Professor M Dowsett PhD (Academic 

Department of Biochemistry) 


FMedSci (Section of Radiotherapy) 

66


Professor J E S Husband OBE FRCP FRCR 

FMedSci (Co-Director, Cancer Research UK 

Clinical Magnetic Resonance Research 

Group) (to June 2005) 


FMedSci (Section of Medicine and Cancer 

Research UK Medical Oncology Unit) 


CPhys FMedSci (Co-Director, Cancer 

Research UK Clinical Magnetic Resonance 

Research Group) 


FRCPCH (Section of Paediatric Oncology) 

(from February 2005) 

Professor K Pritchard-Jones PhD 

FRCPCH FRCPE (Acting Chair of Section 

of Paediatric Oncology) (to February 2005) 


FInstP FIPEM FRSA CPhys CSci 

(Joint Department of Physics) 

Haddow Laboratories 

Professor C S Cooper DSc FMedSci 

(Section of Molecular Carcinogenesis) 

Professor M R Stratton PhD MRCPath 

FMedSci (Section of Cancer Genetics) 

Professor A J Swerdlow PhD DM DSc 

FFPH FMedSci (Section of Epidemiology) 


(Section of Cancer Therapeutics and Director, 

Cancer Research UK Centre for Cancer 

Therapeutics) 

JOINT RESEARCH COMMITTEE 

The Institute and the Royal Marsden 


FMedSci (Chairman) 


Dr G Brown MD MRCP FRCR 

(from February 2005) 

Professor M F Greaves PhD FRCPath Hon 

MRCP FRS FMedSci 


FMedSci 

Professor R S Houlston MD PhD FRCP 

FRCPath 



FMedSci 

Dr C M Nutting MD MRCP ECMO FRCR 





ACADEMIC BOARD 



(Chairman and Academic Dean) 



FMedSci (Chairman and Academic Dean 



(Chief Executive) 

Professor A L Jackman PhD 

(Deputy Dean, Biomedical Sciences) 


FRCPCH FRCPE (Deputy Dean, Clinical 

Sciences) 

Dr J C Bamber PhD (Senior Tutor, Sutton) 

Dr K M Weston PhD (Senior Tutor, Chelsea) 

Dr G W Aherne* PhD 

Mr W H Allum MD FRCS 


Professor D Barford DPhil FMedSci 

Professor J M Bliss FRSS 

Professor M Brada FRCP FRCR 


Professor D Cunningham MD FRCP 

Professor D P Dearnaley MD FRCP FRCR 

Dr N deSouza* MD MRCP FRCP FRCR 

Professor M Dowsett PhD 

Dr S A Eccles* PhD 

Dr R Eeles* PhD FRCP FRCR 

Dr P M Evans* DPhil FInstP FIMA 

Ms C Fang 

Professor C Fisher MD DSc(Med) FRCPath 

Dr G H Goodwin* PhD 

Professor M E Gore PhD FRCP 

Professor M F Greaves PhD FRCPath Hon 



FRCPath 

Dr R A Huddart PhD MRCP FRCR 

Dr D Hudson PhD 


FMedSci 

Professor C Isacke DPhil 


Professor K Jones MA PhD CChem FRSC 

Professor I R Judson MD FRCP 

Dr M Katan* PhD 


FMedSci 


CPhys FMedSci 

Dr C J Lord DPhil 

Dr R Marais* PhD 


FMedSci 

Dr E Matutes* MD PhD FRCPath 

Dr P Meier* PhD 

Dr S Mittnacht* PhD 

Professor G J Morgan PhD FRCP FRCPath 

Professor P S Mortimer* MD FRCP MRCS 

Dr S M Moss* PhD HonMFPH 

Dr L Paon MSc 

Dr G Payne DPhil MInstP MIPEM 

Professor L H Pearl PhD 


FRCPCH 

Professor J Peto DSc HonMFPH FMedSci 

Professor D H Phillips PhD DSc FRCPath 

Professor N Rahman PhD FRCP 

Mr N Rzechorzek BSc(Hons) MRes 

Dr J M Shipley* PhD 

Dr M Smalley PhD 

Professor I E Smith MD FRCP FRCPE 

Dr K Snell* PhD FRSA LRPS 

Professor C J Springer PhD CChem FRSC 


FMedSci 


FFPH FMedSci 

Dr D M Tait MD MRCP FRCR 

Dr G R ter Haar* DSc PhD FIPEM FAIUM 





Professor J R Yarnold MRCP FRCR 

Dr A Z Zelent* MPhil PhD 

*Reader 

FACULTY AND HONORARY FACULTY 


Dr G W Aherne* PhD 

Dr M Ashcroft* PhD 

Professor A Ashworth* PhD FMedSci 

Dr J C Bamber* PhD 

Professor D Barford* DPhil FMedSci 

Professor J M Bliss* FRSS 

Professor M Brada* FRCP FRCR 

Dr L Bruno PhD 

Dr I Collins* PhD 

Professor C S Cooper* PhD DSc FMedSci 

Dr T Crook PhD MBBS MRCP 


Professor D Cunningham* MD FRCP 

Dr D R Dance* PhD FInstP FIPEM CPhys 

Professor D P Dearnaley* MD FRCP FRCR 

Dr J deBono PhD FRCP 

Dr N deSouza* MD MRCP FRCR FRCP 

Professor M Dowsett* PhD 

67


Dr S A Eccles* PhD 

Dr R A Eeles* PhD FRCP FRCR 

Dr T G Q Eisen* PhD FRCP 

Dr P M Evans* DPhil FInstP MIMA 

Professor C Fisher* MD DSc(Med) 

FRCPath 

Dr G Flux* PhD 

Dr M D Garrett* PhD 

Dr G H Goodwin* PhD 

Professor M E Gore* PhD FRCP 

Professor M F Greaves* PhD FRCPath Hon 


Dr E Hall PhD 

Dr K J Harrington PhD MRCP FRCR 

Professor A Horwich* PhD FRCP FRCR 

FMedSci 

Professor R S Houlston* MD PhD FRCP 

FRCPath 

Dr R A Huddart* PhD MRCP FRCR 

Professor J E S Husband* OBE FRCP 

FRCR FMedSci 

Professor C Isacke* DPhil 

Professor A L Jackman* PhD 

Dr C Jones PhD 

Professor K Jones PhD 

Professor I R Judson* MD FRCP 

Dr M Katan* PhD 

Professor S B Kaye* MD FRCP FRCR FRSE 

FMedSci 

Dr R Lamb* PhD 

Professor M O Leach* PhD FInstP FIPEM 

CPhys FMedSci 

Dr S Linardopoulos PhD 

Dr E McDonald* MA PhD ARCS 

Dr R M Marais* PhD 

Professor C J Marshall* DPhil FRS 

FMedSci 

Dr E Matutes* MD PhD FRCPath 

Dr P Meier* PhD 

Dr J Melia* PhD HonMFPH 

Dr S Mittnacht* PhD 

Professor G J Morgan* PhD FRCP 

FRCPath 

Dr E Morris PhD (from April 2005) 

Dr S M Moss* PhD HonMFPH 

Professor R J Ott* PhD FInstP CPhys 


Professor L H Pearl* PhD 

Professor A D J Pearson* MD FRCP 

FRCPCH DCH 

Professor J Peto* DSc HonMFPH FMedSci 

Professor D H Phillips* PhD DSc FRCPath 

Dr C Porter* PhD 

Professor K Pritchard-Jones* PhD 

FRCPCH FRCPE 

Professor N Rahman* PhD FRCP 

Professor P W J Rigby* PhD FMedSci 

Dr J M Shipley* PhD 

Professor I E Smith* MD FRCP FRCPE 

Dr K Snell* PhD FRSA LRPS 

Dr C W So* PhD 

Professor C J Springer* PhD CChem 

FRSC 

Professor M R Stratton* PhD MRCPath 

FMedSci 

Dr A Swain* PhD 

Professor A J Swerdlow* PhD DM DSc 

FFPH FMedSci 

Dr G R ter Haar* DSc PhD FIPEM FAIUM 

Professor S Webb* PhD DIC DSc ARCS 


Dr K M Weston* PhD 

Professor K R Willison* PhD 

Professor P Workman* PhD FIBiol 

FMedSci 

Professor J R Yarnold* MRCP FRCR 

Dr A Z Zelent* MPhil PhD 

* Staff with University of London Teacher Status 

Other Staff who are Teachers of the 

University of London 

Dr P R Blake MD FRCR 

Dr V Brito-Babapulle PhD FRCPath 

Dr G J R Cook MD FRCP FRCR 

Dr J Filshie FFARCS 

Mr G P H Gui MS FRCS FRCSE 

Dr A Hall PhD 

Dr C L Harmer FRCP FRCR 

Dr D L Hudson PhD 

Dr A D L MacVicar MRCP FRCR 

Professor P S Mortimer MD FRCP MRCS 

Dr E C Moskovic MRCP FRCR 


Dr M E R O’Brien MD FRCP 

Dr G Payne DPhil MInstP MIPEM 

Dr F I Raynaud PhD 

Mr P H Rhys-Evans DCC LRCP FRCS 

Dr G M Ross PhD MRCP FRCR 

Dr M F Scully PhD 

Dr P Serafinowski PhD FRSC 


Dr J G Treleaven MD MRCP MRCPath 

Dr M I Walton PhD 

Dr M Watson PhD DipClinPsychol AFBPS 

CORPORATE SERVICES DIRECTORS 

Mr J M Kipling FCA (Secretary of The 

Institute and Head of Corporate Services) 

Mr S Surridge BSc MRICS MBIFM MCMI 

(Assistant Secretary of The Institute & 

Director of Facilities) 

Mrs E Bennett 

(Assistant Company Secretary) 

Mr P J Black (Director of Fundraising) 

Dr S Bright PhD (Director of Enterprise) 

Mr A G Brown 

(Senior Internal Auditor to September 2005) 

Mr J M Harrington BA MSc (Director of IT) 

Mr S J Hobson BA MA (Registrar and 

Director of the Graduate School) 

(from September 2005) 

Mr R G Osborne FCA (Chief of Internal 

Audit) (from October 2005) 

Mrs J Provin MA PGCEA 

(Director of Corporate Development) 

Mrs C Scivier MSc FCIPD 

(Director of Human Resources) 

Dr K Snell PhD FRSA LRPS (Scientific 

Secretary and Director of Research Services) 

Mr A Whitehead ACA (Director of Finance) 

68


The Royal Marsden NHS Foundation Trust 

BOARD OF DIRECTORS 

Non-Executive Directors 

Mrs T Green MA (Chairman) 

Ms F Bates (Vice Chairman) 

(until October 2005) 

Mr J Burke QC 

Mr M Khosla 

Mr S Purvis CBE (until March 2005) 


Mr C Clarke (from May 2005) 

Rev Dame Sarah Mullally 

(from November 2005) 

Executive Directors 



Mr A Goldsman MSc (Health Management) 

ACA (NZ) (Director of Finance and 

Information) 

Professor J Husband OBE FRCP FRCR 

FMedSci (Medical Director) 

Professor D Weir-Hughes 

OStJ EdD MA RN FRSH 

(Chief Nurse/Deputy Chief Executive) 

Other members of the 

Management Executive 

Mrs N French MA MIPD 

(Director of Human Resources) 


(Director of Clinical Research and 

Development) (from November 2005) 


FMedSci (Director of Clinical Research and 

Development) (until October 2005) 

Dr J Milan PhD (Director of Information) 

Mr R D Thomas BSc DMS CEng MICE 

MInstD (Director of Facilities) 

Mrs N Browne (Director of Strategy and 

Service Development) 

Miss F Davies 

(General Manager Common Cancers) 

Miss J Yardley 

(General Manager Rare Cancers) 

Miss F Wheeler 

(General Manager Clinical Services) 

MEDICAL ADVISORY COMMITTEE 


FMedSci (Medical Director – Chairman) 


(Lead Surgeon) (from September 2005) 

Mr D P J Barton MD FRCS MRCOG FACOG 

(Head of Gynaecology Unit) 

(from January 2005) 


(Head of Radiotherapy Services) 

Mr D Chisholm MRCP FRCA (Lead 

Anaesthetist) (from September 2005) 


(Head of Gastrointestinal Unit) 


(Head of Urology Unit) 

Dr R Eeles PhD FRCP FRCR 

(Honorary Consultant in Cancer Genetics 

& Clinical Oncology) 


(Head of Anatomical Pathology Department) 


Mr A Goldsman MSc ACA(NZ) 

(Director of Finance and Information) 


(Divisional Director, Rare Cancers) 

Dr C L Harmer FRCP FRCR 

(Head of Thyroid Unit) (to July 2005) 


FMedSci (Academic Radiotherapy Unit and 

Director of Clinical Research and 

Development) (to September 2005) 

Dr R Huddart PhD MRCP FRCR 

Dr C Irving FRCA (Lead Anaesthetist) 



(Head of Sarcoma Unit) 


(Consultant: Breast & Gynaecology) 


FMedSci (Chairman, Drug and Therapeutics 

Advisory Committee) 

Dr D M King DMRD FRCR 

(Consultant Radiologist) 


(Head of Haematology Unit) 


(Head of Head and Neck Unit) 


(Head of Lung Unit) 




FRCPCH DCH (Head of Paediatric Unit) 



FRCPCH FRCPE (Acting Head of Paediatric 

Unit) (to April 2005) 

Dr J Riley MRCGP (Head of Palliative Care) 

Dr F Saran MD MRCR 

(Consultant Neuro-oncologist) 

Mr J H Shepherd FRCOG FRCS FACOG 

(Consultant Gynaecolgist, Surgeon) 

(to May 2005) 


(Head of Breast Unit) 


(Head of Clinical Audit) 

Mr N Watson MSc MRPharmS MBA 

(Chief Pharmacist) 

Professor D Weir-Hughes OStJ EdD 

MA RN FRSH (Chief Nurse/Deputy Chief 

Executive) 

Mr A C Wotherspoon MRCPath (Head of 

Histopathology Unit) (from December 2005) 

COMMITTEE FOR CLINICAL RESEARCH 


Mr R P A'Hern MSc 

Dr M J Allen MRCP 

Dr A N Davies MSc MD FRCP 


Ms F Davies MSc RN 


Professor M Dowsett PhD (to April 2005) 

Dr T G Q Eisen PhD FRCP 

Dr D Hargrave MRCP FRCPCH 


Dr K J Harrington PhD MRCP FRCR 

Ms H Hollis RN RNT PGDip MSc 


Dr S R D Johnston PhD FRCP (Chairman) 

Dr D Lawrence MA MPhil PhD 

Ms J Lawrence BSc 

Dr I Locke MRCP 

Dr E Matutes MD PhD FRCPath 

Dr A Norman PhD (from October 2005) 

Dr M E R O'Brien MD FRCP 

Dr M N Potter PhD FRCP FRCPath 


Dr F I Raynaud PhD 

Dr S Rogers MRCP FRCR 

Dr F H Saran MD FRCP (from April 2005) 

Dr S A A Sohaib MRCP FRCR 

Mr A C Thompson FRCS 

Mrs C Viner SRN Onc FETC MSc 

69


CLINICAL RESEARCH DIRECTORATE 



FMedSci (Member and Chairman) 

(until October 2005) 




FMedSci 

Dr S R D Johnston, PhD FRCP (Chairman) 



FMedSci 



Dr K Snell PhD FRSA LRPS 

(Joint Scientific Secretary) 

CONSULTANTS AND HONORARY 

CONSULTANTS 

Anaesthetics 

Dr G P R Browne DA FFARCS 

Dr D Chisholm MRCP FRCA 

Dr W P Farquar-Smith PhD FRCA 

Dr J Filshie FFARCS 

Dr M Hacking FRCA 

Dr C J Irving FRCA 

Dr J J Kothari FFARCS 

Dr A Oliver FRCA 

Dr J E Williams FRCA 

Dr C Carr DA FRCA DICM 

Dr D Burton FRCA (Locum to August 2005) 

Dr P Suaris FRCA (Locum to August 2005) 

Dr J Mitic MD DEAA FFARCSI (Locum) 

Dr O J Lacey FRCA (from July 2005) 

Cancer Genetics 

Dr R A Eeles PhD FRCP FRCR 


FRCPath 

Professor N Rahman PhD MRCP 


FMedSci 

Drug Development 


Dermatology 

Dr C Bunker MD FRCP 

Professor P S Mortimer MD FRCP MRCS 

Epidemiology 


FFPH FMedSci 

General Surgery 


Professor Sir A Darzi FRCS FMedSci 

(from November 2005) 

Mr S R Ebbs MS FRCS 

Mr G P H Gui MD FRCS FRCSEd 

Mr A J Hayes FRCS PhD 

Mr M M Henry FRCS 

Mr J M Thomas MS MRCP FRCS 

Mr G Querci-della-Rovere MD FRCS 

Mr J N Thompson FRCS 

Gynaecology 

Mr D P J Barton MD FRCS MRCOG FACOG 

Ms J E Bridges MRCOG 

Mr T Ind MD MRCOG 

Mr J H Shepherd FRCOG FRCS FACOG 

Haematology 

Dr C E Dearden MD MRCP MRCPath 

Dr M E Ethell MRCP MRCPath 


Dr E Matutes MD PhD FRCPath 

Dr M N Potter PhD FRCP FRCPath 

Dr J G Treleaven MD MRCP MRCPath 

Histopathology and Cytopathology 

Dr N Al-Nasiri FRCPath (to June 2005) 


Dr A Y Nerurkar MD DNB 

Dr P Osin MD MRCPath 

Mr A C Wotherspoon MRCPath 

Medical Microbiology 

Dr U Riley MRCP MRCPath 

Medical Oncology 


Dr J deBono PhD FRCP 

Dr T G Q Eisen PhD FRCP 




FMedSci 


Dr M R Scurr BMed FRACP 

(Locum from November 2005) 


Dr H J N Andreyev MA PhD MRCP 

(Locum from September 2005) 

Dr G Chong MD FRCP (Locum) 

Nuclear Medicine 

Dr G J R Cook MD FRCP FRCR 

Professor R Underwood MD FRCP FRCR 

FESC 

Dr V Lewington FRCP 

Occupational Health 

Dr B J Graneek MRCP AFOM 

Ophthalmology 

Mr R A F Whitelocke PhD FRCS FRCOphth 

Oral Surgery 

Mr D J Archer FDSRCS FRCS 

Otolaryngology 

Mr P M Clarke FRCS 

Mr P H Rhys-Evans DCC LRCP FRCS 

Paediatrics 

Dr A Albanese MD MRCP MPhil 

Dr D R Hargrave MRCPCH 

Dr D L Lancaster MD MRCP(UK) MRCPH 


FRCPCH 


FRCPCH FRCPE 

Dr M M Taj FMGEMDCH MRCP 

Dr S Vaidya DCH MD (Paediatrics) MD 

(Locum from October 2005) 

Palliative Medicine 

Dr A Davies MD MRCP 

Dr J Riley MRCGP FRCP 

Dr A Jennings MRCGP FRCP 


Psychological Medicine 

Dr M Watson PhD DipClinPsychol AFBPS 

Radiology 

Dr G Brown MD MRCP FRCR 

Dr N deSouza MD FRCR FRCP 


FMedSci 

Dr P Kessar MRCP FRCR (to March 2005) 

Dr D M King DMRD FRCR 

Dr M Koh MRCP FRCR 

Dr A D L MacVicar MRCP FRCR 

Dr E C Moskovic MRCP FRCR 

Dr B Sharma FRCR BMMRCP 

Dr S A A Sohaib MRCP FRCR 

Dr R Pope MRCP FRCR 

Radiotherapy 


Professor M Brada FRCP FRCR 


Dr J P Glees MD FRCR DMRT 


FMedSci 


Dr V S B Khoo MD FRACR 

Dr C M Nutting PhD MRCP ECMO FRCR 

Dr C Parker MD MRCP FRCR 

Dr G M Ross PhD MRCP FRCR 

Dr A Y Rostom DMRT FRCR 

Dr F Saran MD MRCR 


Professor J R Yarnold MRCP FRCR 

Dr A Drury LRCP MRCS FRCR 

(Locum from September 2005) 

Reconstructive Surgery 

Mr A Searle FRCS FRCS(Plast) 

Mr P A Harris MD FRCS(Plast) 

Urological Surgery 

Mr T Christmas MD FRCS 

Mr A C Thompson FRCS 

Professor C R J Woodhouse FRCS FEBU 

70



NHS Foundation Trust 

Chelsea 

Chester Beatty Laboratories 

237 Fulham Road 

London SW3 6JB 

Tel: 020 7352 8133 

Sutton 

15 Cotswold Rd 

Sutton 

Surrey SM2 5NG 

Tel: 020 8643 8901 

Chelsea 

Fulham Road 

London SW3 6JJ 

Tel: 020 7352 8171 

Sutton 

Downs Road 

Sutton 

Surrey SM2 5PT 

Tel: 020 8642 6011 

Secretary’s Office and Registered Office 


123 Old Brompton Road 

London SW7 3RP 

Tel: 020 7352 8133 

www.royalmarsden.nhs.uk 

www.icr.ac.uk 

Published by Research Services 


123 Old Brompton Road, London SW7 3RP 

© The Institute of Cancer Research and 

The Royal Marsden NHS Foundation Trust 2006 

ISBN 0-905986-29-X 

Designed by Causeway Communications 

causewayco@aol.com 

Printed in Great Britain by 

Lundie Brothers Ltd, Croydon CR0 2DP 

The review period covered by the Annual Research Report is 1 January to 31 December 2005. 

Copies of previous Research Reports and The Institute’s Annual Review for 2005 may be obtained from: 

The Secretary, The Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP. 

Copies of the Annual Report for 2005/2006 of The Royal Marsden NHS Foundation Trust may be obtained from: 

The Press Office, The Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ. 

71

Joint Annual Research Report 2005 - The Royal Marsden

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