What Keeps Cancer Drug Developers Awake at Night
This article was originally published in Start Up
Executive Summary
The range of comments, as well as the general tone, of a recent clinical cancer meeting prompted us to ask developers of cancer drugs what they saw as the major issues and hurdles in designing and testing new compounds. Their comments suggest that empirical methodologies, albeit informed by understanding of the biology around a target, will dominate clinical thinking in the near term. Clinical setbacks over the past several years, a lack of validated biomarkers, and an awareness that preclinical models are of limited utility in establishing dose and identifying likely responders, have reinforced that perception. Developers' principal concerns therefore often focus on things that are within their control; in particular, how to resource and manage a program for the long haul.
You may also be interested in...
A New, Compelling Reason to Target Hsp90 in Tumor Cells
The finding that hsp90, a "molecular chaperone" that shuttles proteins throughout cells and performs a critical role in the mitochondria of tumor cells could have a profound influence on the development of an emerging class of drugs. It may help explain the limited effectiveness of current hsp90 inhibitors, which do not get into the mitochondria. The authors of the paper describing the work show that an hsp90 inhibitor that does get into the mitochondria has profound cell-killing capabilities.
AstraZeneca's Iressa Problem
In May of this year, two major scientific journals published papers correlating response to Iressa, AstraZeneca's targeted therapy for refractory non-small cell lung cancer, to a series of mutations clustered in a section of the EGFR gene. These widely publicized findings are fueling discussions that are bound to have consequences not only for AstraZeneca, patients and clinicians, but also for many pharmaceutical companies working on targeted therapies.
The Fits and Starts of Targeted Cancer Drug Development
Despite the success of Gleevec, developing drugs that inhibit complex signaling pathways, while simultaneously trying to understand the biology around a drug's target, remains a challenge. Without biomarkers to help establish dosing and identify likely responding patients, clinical development of targeted cancer drugs will remain challenging. AstraZeneca's recent experience with Iressa bears this out. It's likely that single markers will not be sufficient to stratify patients by their tumor types; rather, patterns of gene and protein expression will be required. The technology to take these measurements is making its way from academia to industry, but the process is slow, and needs encouragement and better coordination between academia, regulators, and industry. Meanwhile, clinical trials themselves remain the best target validation tools. When all is said and done, efficacy is the best biomarker.