Drug Development: Portals of Discovery

Abstract

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.

BRAF Inhibitors for the Treatment of Metastatic Melanoma: Clinical Trials and Mechanisms of Resistance

“…By comparison, sorafenib and RAF-265, 2 broad-spectrum kinase inhibitors (with BRAF being among the kinases inhibited), produced minimal evidence of tumor regression and achieved only modest MAPK pathway inhibition at their maximum tolerated doses (17,18). [For a discussion about the pitfalls encountered in the development of targeted therapies, see the article by Bates and colleagues (19) in this CCR Focus section.] The selectivity of vemurafenib and dabrafenib likely accounts for the disparate results, because BRAF is inhibited to a far greater degree than other kinases.…”

The Insulin Receptor/Insulin-Like Growth Factor Receptor Family as a Therapeutic Target in Oncology

“…It has been pointed out that, in general, clinical trials should take into account the possibility of benefit confined to patient subgroups (74), and this has not been explored in detail in the case of therapies that target the insulin/IGF-I receptor family. This issue is a common one in cancer drug development (75,76).…”

The Urgent Need for Clinical Research Reform to Permit Faster, Less Expensive Access to New Therapies for Lethal Diseases

“…As examples, the simple fact that cancer is increasingly recognized as comprising a multiplicity of genetic subsets, and the fact that we have pursued many targets that were not properly and adequately validated, are not the topics of this treatise. These topics are covered elsewhere in this (9,10) and earlier editions (11) of CCR Focus. Rather, we will focus on aspects of drug development that we as a community have much more control over.…”