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'Synthetic lethality' strategy improves molecularly targeted cancer therapy
Date:9/21/2010

PHILADELPHIA (September 21, 2010)Molecularly targeted therapies can reduce tumors rapidly. However, not all tumors respond to the drugs, and even those that do often develop resistance over time. Looking for a way to combat the problem of resistance, researchers at Fox Chase Cancer Center hypothesized that hitting already weakened cancer cells with a second targeted agent could kill thembut only if it was the right second agent.

One well-validated molecular target for anti-cancer drugs is the epidermal growth factor receptor, or EGFR. Using a novel screening approach, investigators in the Fox Chase Developmental Therapeutics Program identified over 60 additional proteins that are necessary for cells to survive in the presence of an EGFR inhibitor. When they simultaneously blocked the EGFR inhibitors and any one of these other proteins, more of the cancer cells died. The researchers say this screening strategy to identify targets for effective combinations of cancer drugs will open the door for future therapies. Already, two clinical trials are under way to test innovative drug combinations suggested by the new tactic.

"We found that knocking out one or the other target doesn't have a major effect, but knocking out both increases tumor cell death," says Igor Astsaturov, M.D., Ph.D., an assistant professor and medical oncologist at Fox Chase. Astsaturov led the study, which will be published in the September 21, 2010 issue of Science Signaling.

To identify additional targets that would boost the effectiveness of EGFR inhibitors against cancer, Astsaturov and colleagues screened only proteins that interact directly or indirectly with EGFR. The team mined the literature and built a candidate set of 638 EGFR-interacting proteins. They then used an experimental technique called small inhibitory RNA (siRNA) systematically to block activity of each of the genes in cancer cells that had been treated with an EGFR inhibitor. In doing so
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Contact: Diana Quattrone
Diana.Quattrone@fccc.edu
215-728-7784
Fox Chase Cancer Center
Source:Eurekalert

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