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.