The plummeting cost of DNA sequencing has enabled scientists to explore the genetic complexities of cancer with an ever-finer comb, uncovering a growing number of genetic mutations that drive cancer. Now this genetic knowledge is being used to direct drug development by testing specific compounds on 1,000 cancer cell lines that incorporate many of these mutations. The findings will help pharmaceutical companies design clinical trials so that they include only those patients most likely to respond to a drug. Ultimately, physicians hope to be able to screen a patient’s tumor and choose the most effective drug based on its specific genetic profile.
While a number of molecularly targeted cancer drugs, such as gleevec and herceptin, are already on the market, the effectiveness of most of these drugs depends on a single genetic mutation or molecular marker in the tumor. Scientists say that incorporating the diversity of cancer genomics in much greater detail will enable more personalized treatment for a broader number of patients.
“Understanding the ways in which the individual genomes of cancers are broken is key to effective treatment, particularly with molecularly targeted agents,” says Andy Futreal, codirector of the Cancer Genome Project at the Wellcome Trust Sanger Institute, in Hinxton, U.K. Futreal is overseeing the largest study yet to correlate genetics with response to cancer drugs, in collaboration with scientists at Massachusetts General Hospital.
Researchers will screen 400 compounds on 1,000 lines of cancer cells derived from a variety of types of tumors. (Previous efforts to screen new drugs on cancer cell lines have focused on just tens of different lines.) Collectively, the cells possess about 70 cancer-linked genetic mutations, about 50 to 80 percent of the mutations that have been uncovered to date. “The extent of our genomic characterization is unmatched,” says Cyril Benes, director of The Center for Molecular Therapeutics at Mass General. “It is this combination of extensive data sets that permits us to look at multiple factors influencing drug response.” Eventually, scientists aim to sequence the entire protein-coding region of all the cell lines, enabling even more comprehensive analysis.
“Oftentimes, there may be multiple mutations that you need to read together to determine if a drug is effective or not,” says Levi Garraway, a researcher at the Broad Institute, in Cambridge, MA. Garraway is starting a similar screening study in collaboration with the Swiss pharmaceutical company Novartis.
The compounds to be screened in the Mass General/Wellcome study include both traditional chemotherapies, which can affect both healthy and cancerous tissue, and molecularly targeted drugs, designed to attack a particular genetic flaw specific to cancer cells. The researchers are also working with drug companies to test novel compounds that are either in or close to early stage clinical testing. Pharmaceutical companies can use the results to define the genetic profile of patients most likely to respond to the drug. Focusing clinical trials in this manner should speed up the process, and may even allow the approval of drugs that would have failed in the broader population. “I think that’s the big drive for them to come to us,” says Benes.
Initial results of the study, released last week, identified some previously known cancer mutations, such as a gene called BRAF, that affect drug efficacy, confirming that the approach works. Earlier work showed that mutations in this gene affect how well melanoma patients respond to certain drugs. “But we have much more complex analysis going on that shows combinations of mutations that appear to drive response,” says Benes. Researchers are making the data publicly available.
The findings may also aid development of diagnostic tests designed to capture a genetic snapshot of an individual’s tumor. Foundation Medicine, a startup based in Cambridge, MA, is developing one such test. “The objective is to generate diagnostic tests that are comprehensive, consolidating information on particular genetic alterations now associated with drug response and resistance into a single test, so you don’t have to do dozens of tests,” says Garraway, one of the company’s cofounders. “Those who work at Foundation will be keeping eye out on results from these resources to determine whether markers that emerge should be part of such a test.”