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Apotherapy<br />
CD40 ligand-based modalities for the<br />
treatment of cancer<br />
Summary<br />
Keywords | <strong>Cancer</strong> | gene therapy | signalling | apoptosis | CD40 | phosphoinositide 3-kinase | metastasis |<br />
<strong>Cancer</strong> is a major disease according to the WHO Mortality<br />
Data base (2004) and is responsible for approximately 25 %<br />
of all deaths in the European Union. Epithelial tumours, such<br />
as those of the ovary, lung and oesophagus, have particularly<br />
poor prognosis, with only a minority of patients achieving<br />
a fi ve-year survival. Conventional treatments, including<br />
chemotherapy and radiotherapy, have limited effi cacy and<br />
frequently cause severe side-eff ects in patients.<br />
The Apotherapy project brings together expertise from academic<br />
and biotechnology sectors across seven European<br />
countries with the aim of developing and validating novel<br />
anti-cancer agents with a wide therapeutic index and minimal<br />
side-eff ects. The focal point of our research is the<br />
utilisation of combined approaches which attack the tumour<br />
cell at multiple levels, achieving maximal apoptosis while<br />
limiting the risk of drug resistance. These approaches involve<br />
the effi cient delivery of a pro-apoptotic molecule to cancer<br />
cells in combination with inhibitors of anti-apoptotic signal<br />
transduction pathways.<br />
Specifi cally, the project will formulate therapeutic strategies<br />
which exploit the ability of CD40 ligand (CD40L), a TNF<br />
family member, to reduce proliferation, promote apoptosis<br />
and activate anti-tumour immune responses selectively in<br />
cancer cells. Apotherapy will develop state-of-the-art vehicles<br />
for the effi cient delivery of CD40L to cancer cells, such<br />
as CD40L-encapsulated liposome formulations and recombinant<br />
adenoviruses expressing CD40L, and examine their<br />
in vitro and in vivo eff ects on tumour cell growth and<br />
metastasis.<br />
Apoptosis induced by CD40 engagement is dramatically<br />
augmented in the presence of inhibitors of the phosphoinositide<br />
3-kinase (PI3 kinase) pathway, which is frequently<br />
found activated in human tumours. The Apotherapy project<br />
will expand on the development of novel PI3 kinase antagonists<br />
and evaluate their in vitro and in vivo capacity to kill<br />
tumour cells and to amplify the CD40L-mediated eff ects on<br />
carcinoma cell growth, angiogenesis and metastasis.<br />
Problem<br />
<strong>Cancer</strong> has a major health, social and fi nancial impact on<br />
Europe and its people. Current treatments include primary<br />
tumour resection and/or aggressive chemotherapy and radiotherapy<br />
in order to achieve both local control and eff ective<br />
therapy for distant metastases. Despite improved therapeutic<br />
regimens, mortality rates are still high. Moreover, the<br />
frequency of cancer incidence is predicted to increase and,<br />
as a result, its social and economic toll may reach even higher<br />
levels in the next decades. The growing cancer burden in<br />
Europe underscores the need to develop more effi cient antitumour<br />
agents with a view to increasing survival and<br />
improving the quality of life of cancer suff erers.<br />
Aim<br />
Apotherapy aims to combat cancer through an innovative<br />
combination strategy which targets cancer cells at multiple<br />
levels. One arm of this strategy is to encourage carcinoma<br />
cell apoptosis and immune recognition through the optimal<br />
activation of the CD40 pathway and the other is to suppress<br />
tumour cell survival mediated by the PI3 kinase signaling<br />
pathway. This strategy has been designed to achieve maximal<br />
inhibition of tumour growth while limiting the risk of<br />
side-eff ects.<br />
Expected results<br />
• The Apotherapy project will provide new information<br />
about targeting the CD40 and PI3 kinase pathways in<br />
solid tumours.<br />
• The project will develop and evaluate viral and non-viral<br />
vectors for the effi cient and tumour-specifi c delivery of<br />
anti-cancer agents in vivo.<br />
• Apotherapy will characterise novel antagonists and inhibitors<br />
of the anti-apoptotic PI3 kinase signalling pathway.<br />
• An extensive pre-clinical evaluation of CD40L delivery systems<br />
in combination with PI3 kinase pathway antagonists<br />
will be performed, aided by in vivo imaging technology.<br />
Potential applications<br />
The Apotherapy project will lead to the development of novel<br />
anti-cancer strategies which will be directly applicable to the<br />
clinic for the benefi t of cancer suff erers. The strong focus on<br />
translational research will translate R&D results into tangible<br />
benefi ts for health, science and economy in Europe.<br />
166 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
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