Drug development: portals of discovery.

摘要

A British humorist said, "There is much to be said for failure. It is much more interesting than success." This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf-mutated melanoma and crizotinib for non-small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a number of other pathways has been slower and less successful. These agents include drugs for blocking the insulin-like growth factor I/insulin receptor pathways, mitotic kinase inhibitors, and Hsp90 antagonists. Several potentially useful, if not groundbreaking, agents have had setbacks in clinical development, including trastuzumab emtansine, gemtuzumab ozogamicin, and satraplatin. From experience, we have learned the following: (i) not every altered protein or pathway is a valid anticancer target; (ii) drugs must effectively engage the target; (iii) the biology of the systems we use must be very well understood; and (iv) clinical trials must be designed to assess whether the drug reached and impaired the target. It is also important that we improve the drug development enterprise to enhance enrollment, streamline clinical trials, reduce financial risk, and encourage the development of agents for niche indications. Such enormous challenges are offset by potentially tremendous gains in our understanding and treatment of cancer.