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BioCare<br />
Molecular Imaging for Biologically<br />
Optimised <strong>Cancer</strong> Therapy<br />
Summary<br />
Early tumour detection and response monitoring require<br />
maximum sensitivity and specifi city of the imaging method.<br />
This project focuses on the clinical evaluation and development<br />
of new, more specifi c molecular tracers for the early<br />
detection of tumour cells. A large number of new and<br />
potentially more specifi c tracers than fl uorodeoxy-glucose<br />
(FDG) will be tested, including amino acid analogues, small<br />
tumour-binding peptides, aptamers, peptides binding to<br />
mutant p53 proteins and nanoparticles. The more tumour<br />
specifi c the tracer, the more accurately it will be possible to<br />
image the true tumour cell density and, more importantly,<br />
the true response of the tumour to therapy.<br />
There is also a need to consolidate experience in the use of<br />
recently developed molecular tracers to assess radiotherapy<br />
and chemotherapy response in order to improve on<br />
state-of-the-art treatments. To maximise the sensitivity and<br />
tumour image quality, a high-resolution, wide fi eld-of-view,<br />
ultra-sensitive fully integrated PET-CT camera, capable of<br />
imaging half the human body in a few minutes, will be<br />
designed. Furthermore new adaptive therapy planning and<br />
biological optimisation codes and a dedicated PET-CT<br />
detector for incorporation in treatment units will be designed<br />
in close corporation with university researchers and SMEs.<br />
This will allow an effi cient clinical integration and high<br />
patient throughput. The associated increase in accuracy of<br />
tumour imaging and the three-dimensional in vivo tumour<br />
responsiveness data will hopefully allow the clinical introduction<br />
of accurate biologically based adaptive treatment<br />
optimisation methods.<br />
Problem<br />
Keywords | Molecular tumour imaging | cancer therapy | PET-based treatment planning | PET-CT simulation |<br />
apoptosis | tumour hypoxia | aptamers | PET-CT-RT | diagnostic treatment unit |<br />
<strong>Cancer</strong> imaging is at the dawn of a third revolution of accurate<br />
tumour diagnostics. During the 1970s and early 1980s,<br />
computed tomography (CT) with diagnostic X-rays made<br />
a revolution in accurate delineation of normal tissue anatomy<br />
as well as gross tumour growth. In the mid 1980s and<br />
1990s, magnetic resonance imaging and spectroscopy (1.2)<br />
allowed even more accurate diff erential diagnostics of soft<br />
tissue malignancies with the possibility of distinguishing<br />
between tumour tissues, oedema and normal tissues. The integration<br />
of positron emission and X-ray computed tomography<br />
in one unit and MRSI – MR spectroscopic imaging – is bringing<br />
a third diagnostic revolution to tumour imaging. By combining<br />
these two imaging modalities, an unprecedented accuracy in<br />
the delineation of the tumour on a background of normal<br />
tissue anatomy is achieved.<br />
Obviously, fl uorodeoxyglucose (FDG) is not tumour-specifi c,<br />
as all regions with an increased metabolic rate will show an<br />
elevated uptake. However, in the new era of molecular imaging<br />
it is likely to be followed by more specifi c tumour<br />
markers, allowing an even more accurate imaging of the<br />
tumour clonogen density. Methionine and other amino acids<br />
are already available as tracers and, although they may be<br />
better than FDG, they may still not be suffi ciently specifi c,<br />
since they are incorporated in all tissues that are being<br />
renewed. For some tumours, there are more specifi c markers<br />
such as 11 C-Choline, and FHBC or FDHT (fl uorodihydrotestosterone)<br />
for imaging androgen receptors in prostate<br />
cancer. Vasculature could be visualisable by known tracers<br />
such as ammonia ( 11 CH 3 ) or water (H 2 15 O).<br />
Aim<br />
Molecular imaging of radiation-induced alteration of tumour<br />
cell proliferation and functional receptor expression. In<br />
recent years, radiotracer-based molecular imaging with<br />
positron emission tomography in oncology has evolved as a<br />
valuable tool for staging of disease and evaluation of therapy<br />
response. This success is mainly based on the application<br />
of the glucose analogue 18Fluorodeoxyglucose, which traces<br />
tumour tissue by the fact that most tumours exhibit<br />
enhanced glucose consumption. But the tumour microenvironment<br />
is not depending only on glucose metabolism.<br />
Perfusion, hypoxia, amino acid uptake and receptor status<br />
are important parameters which have high impact on the<br />
treatment success. Additionally to ‘the classics’, FDG and<br />
methionine, new PET-tracers to monitor these parameters<br />
are under development. With the advent of high-resolution<br />
animal PET scanners there is now the opportunity to investigate<br />
in vivo the tumour microenvironment of transplanted<br />
tumours in small animals under therapy conditions, especially<br />
for radiation therapy – for example the knowledge on<br />
the course of oxic or hypoxic conditions has the potential to<br />
develop strategies to overcome treatment failure due to<br />
hypoxia-related radiation resistance. PET off ers the opportunity<br />
to investigate the radiation response of tumours<br />
longitudinal during the treatment time, to evaluate the predictive<br />
strength of diff erent parameters or their combination,<br />
and to test the effi cacy of newly developed tracers in comparison<br />
to ‘standard tracers’. The functional PET data will be<br />
supplemented by tumour histology, immunohisto-chemistry<br />
and autoradiography to complement the tumour-pathophysiologic<br />
data.<br />
In the future we thus need improved tracers to the image<br />
tumour spread before treatment. This will enable accurate<br />
delineation of the clinical target volume based on visualised<br />
uptake by the tumour, for example along well-known pathways<br />
of microscopic lymphatic invasion.<br />
108 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME