A new screening technique can rapidly identify chemical compounds that are active only in the presence of certain carcinogenic alleles and their proteins, according to an article in the March 24th issue of Cancer Cell. Development of the test, which pairs compounds with specific alleles, may be a new approach toward the goal of genetic customization of chemotherapy for individual patients.

The American researchers started with human cancer cells engineered to contain a selection of common carcinogenic alleles, including the ras and htert oncogenes, and two known oncoproteins. The screening assay exposed the cells to over 23,000 compounds; eventually, investigators identified 9 compounds that showed activity only in the presence of the target mutations and proteins.

"Using this system, we searched for compounds that become active only in the presence of commonly mutated genes," said Brent Stockwell, Ph.D., senior author of the study. "We've identified several compounds, including one previously unknown compound that had exactly the effect we were looking for."

Mass screening, also called high-throughput testing, represents a new and emerging model for drug discovery. "The old method to find drug candidates was to take tumor cells from a human tumor and find things that killed them, without really understanding how they would ultimately affect other cells in the body," Stockwell explained. "Drug candidates identified by this method often turned out to be completely toxic to healthy cells and thus, not usable as a therapy."

Of the 9 selectively active compounds, 4 are currently used in clinical practice to treat tumors. A better understanding of how these drugs work may offer vital insight into which drugs are more likely to be effective against a particular type of cancer. "We discovered that these anticancer drugs are particularly effective in tumor cells with specific genetic changes, suggesting a strategy by which we can tailor the use of these drugs to fit a patient's unique tumor type," noted Stockwell.

One of the previously unidentified compounds had never been studied as a potential chemotherapeutic agent. The investigators have called it erastin. Erastin is especially interesting because it does not appear to trigger apoptosis. "The most immediate thing is to figure out how erastin works and try to understand that molecular mechanism in detail," Stockwell concluded.