Drugs for solid cancer: the productivity crisis prompts a rethink

Despite remarkable progress in cancer-drug discovery, the delivery of novel, safe, and sustainably effective products to the clinic has stalled. Using Src as a model, we examine key steps in drug development. The preclinical evidence on the relationship between Src and solid cancer is in sharp contrast with the modest anticancer effect noted in conventional clinical trials. Here, we consider Src inhibitors as an example of a promising drug class directed to invasion and metastasis and identify roadblocks in translation. We question the assumption that a drug-induced tumor shrinkage in preclinical and clinical studies predicts a successful outcome. Our analysis indicates that the key areas requiring attention are related, and include preclinical models (in vitro and mouse models), meaningful clinical trial end points, and an appreciation of the role of metastasis in morbidity and mortality. Current regulations do not reflect the natural history of the disease, and may be unrelated to the key complications: local invasion, metastasis, and the development of resistance. Alignment of preclinical and clinical studies and regulations based on mechanistic trial end points and platforms may help in overcoming these roadblocks. Viewed kaleidoscopically, most elements necessary and sufficient for a novel translational paradigm are in place.