NCI Explains a New Paradigm for Drug Development
August 19, 2008
Until recently, cancer drug development has focused on cytotoxic compounds. These drugs kill cancer cells, but they can also kill normal cells, leading to the toxic side-effects of traditional chemotherapy. But recent leaps in understanding of the molecular events that drive a cell to become cancerous have led researchers to agents that specifically target molecular traits of cancer cells. Most targeted agents do not kill cancer cells. Instead, they stop them from growing.
Such targeted agents now make up the majority of anticancer drugs under development. "If you look at the current pipeline right now, not counting clinical development, it's probably two-thirds targeted agents and one-third traditional cytotoxic agents. Five years ago that ratio was reversed," says Dr. James Doroshow, director of NCI's Division of Cancer Treatment and Diagnosis (DCTD).
Targeted drug development presents a whole new set of challenges to researchers working on drug discovery. "If you're looking for a cytotoxic drug, then a compound that kills a tumor cell would be a candidate. With a targeted agent, you actually have to know what molecular pathway you're interested in in the first place," explains Dr. Joseph Tomaszewski, deputy director of DCTD. "You need a clear understanding of how disregulation or mutation of a target-for example, a protein or gene-has an impact on the formation, growth, and metastasis of various types of tumors."
DCTD and other divisions in NCI are responding to the need for newer screening techniques designed specifically for targeted agents. One project is extending the capabilities of the NCI-60 cell screen, which has been used for more than 15 years to screen for cytotoxic compounds. "We're trying to understand how new [targeted] drugs affect the expression of a large number of genes in those cells-say, 30,000 genes across 50 or 60 different cell types; that is, we're trying to understand whether we can use the NCI-60 as a functional genomic screen" to understand how new drugs affect cancer cells on a molecular level, explains Dr. Doroshow.
Through NCI's Mouse Models of Human Cancers Consortium (NCI-MMHCC), NCI is building relationships and developing private partnerships to further the use of mouse models in preclinical testing of agents from pharmaceutical and biotechnology companies.
"A number of companies are providing their lead compounds to Consortium laboratories to test them in a variety of cancer models," says Dr. Cheryl Marks, associate director for NCI's Division of Cancer Biology and the NCI-MMHCC program director. "This is one way to familiarize the private sector with use of genetically engineered mice in their preclinical research. The goal is to enable the companies to identify tumor sites that would be the most promising choices for phase II and III clinical trials."
Another major need in targeted drug development is for reliable, reproducible pharmacodynamic measurements-measurements of how drugs are affecting the molecular workings of cells in the body. "A lot of the pharmacodynamic assays that scientists have been using for years work to a certain extent but have not been rigorously developed and standardized. As a result, you do not have absolute confidence in the data," says Dr. Tomaszewski. "We've embarked on creating more standardized assays that will allow us to make earlier decisions about whether or not we're having an impact on a target; and in that way, you can establish an earlier stage whether you will continue down the development pathway or not continue with a particular agent. Once you move beyond the preclinical efforts, you're spending a tremendous amount of money. If you drug fails late in the phase III studies, it wastes a tremendous amount of resources."
Reprinted from the NCI Cancer Bulletin, Aug. 19, 2008, Vol. 4, No. 17, pg 4.