Applications of Dynamic Contrast-Enhanced MRI in Oncology Drug Development

Approximately one third of the American and European population will develop cancer at some time in their lives. The incidence of cancer increases with age, and among middle-aged people cancer is the single greatest cause of mortality. Currently the major treatment options are surgery, radiotherapy, cytotoxic chemotherapy and hormonal modulation. Despite the tremendous improvements in cancer treatment over the past few decades, survival rates for many cancers are still poor and cytotoxic chemotherapy is usually accompanied by signifi cant toxicity. There remains a huge unmet medical need for better cancer therapies. Entirely novel anti-cancer drugs are under development. With the explosion in our understanding of the molecular biology of cancer, hundreds of potential molecular targets have been identifi ed for anticancer drugs beyond the traditional antiproliferative agents. Potential drug targets have been identifi ed in receptors, enzymes and associated biochemical pathways, in areas such as angiogenesis and tumour perfusion, the cell cycle, apoptosis, invasion and growth factors. Targets identifi ed in angiogenesis and the tumour vasculature (Cristofanilli et al. 2002) include the signalling pathways responsible for the growth of new blood vessels, together with factors required for the survival and structural integrity of immature endothelium. Vascular targets are particularly attractive, since effects on a small number of endothelial cells may affect the nutrition of a large number of tumour cells and, because the cancer cell itself is not targeted, the problem of resistance may be reduced. Medicinal chemists and molecular biologists have been highly successful at devising candidate drugs with good activity in preclinical testing against targets in the tumour vasculature. Dozens of such molecules are now in clinical trial, and hundreds more are in pre-clinical evaluation. These candidate drugs include orally bioavailable, rationally designed, small organic molecules, as well as biological agents that would typically require parenteral administration, for example neutralising antibodies. The clinical development of these newer types of agent poses new challenges. Unlike antiproliferative drugs, they will not inevitably show acute dose-limiting toxicity. In addition the anti-angiogenic compounds are likely to be cytostatic rather than cytotoxic, and thus tumour stabilisation rather than response is a more probable outcome, at least with monotherapy. Considerable ingenuity may be required to devise a development programme that effectively identifi es the best candidate drug molecule CONTENTS