52 - Discovery and Development of Drugs Targeting Tumor Invasion and Metastasis

Summary

THE ERA OF MOLECULAR TARGETED THERAPY

Efforts to discover and develop novel molecular targeted cancer treatments that commenced in many pharmaceutical companies in the early 1990s have begun to make significant contributions to patient survival. Small-molecule and antibody therapeutics against targets such as EGFR (e.g. cetuximab, erlotinib, gefitinib), erbB2 (trastuzumab, lapatinib), VEGFR (bevacizumab, sorafenib, sunitinib, pazopanib, vandetanib), Abl (imatinib, nilotinib), and mTOR (sirolimus, temsirolimus) have delivered clinical efficacy in certain disease settings. The emergence of these therapies has led to an era of treatments increasingly targeted to selected patient populations, and this has implications for the development of future novel treatments [1–3]. As outcomes improve, increasingly demanding goals are set for new drugs to achieve, both preclinically and in clinical trials.

The majority of small-molecule and antibody agents to date have focused attention on proliferation, survival, and angiogenic pathways. Although there are examples of drugs targeting c-met, TGFβ src, and FAK that have progressed to clinical trials (Table 52.1), there has been relatively little commercial activity specifically targeted against the molecules and pathways contributing to the invasive phenotype and the process of metastasis. Whereas key cell proliferation and survival pathways may ultimately have an impact on metastasis [4–6], it is also clear, from much that has been discussed elsewhere in this volume, that there are targets and pathways not currently exploited, and that disease progression could be modified by modulating the underlying mechanisms contributing to tumor invasion and metastasis.