prostate cancer discovery

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the patrick c. walsh prostate cancer research fund

Who Can Benefit from Drugs That Stop Cancer Cells from Repairing Themselves?

Anthony Leung, Ph.D., an RNA biologist, is interested in drugs that inhibit PARP. PARP — which stands for poly (ADP- ribose) polymerase — inhibitors have shown promise in treating ovarian, breast, and prostate cancers. "These drugs are designed to target cancers that already have defects in their ability to repair DNA, and rely on remnant repair pathways for survival," he says. "These remnant pathways are mediated by PARP; so by blocking these pathways, scientists can kill cancer cells but spare healthy cells with functional DNA repair." PARP-inhibiting drugs have been shown to extend life and even cause tumors to go into remission in patients with mutations in the DNA repair genes BRCA 1 and 2. "PARP inhibitors have also shown survival benefits for other patients with difficult-to-treat, castration-resistant prostate cancers," says Leung. In an ongoing Phase II trial of Olaparib, men with advanced, castration-resistant prostate cancer have shown impressive responses, he adds. "This trial includes patients who have not inherited BRCA mutations, but do carry mutations to DNA repair genes within their tumors. These encouraging data suggest the possibility of expanding access to PARP inhibitors to patients with other defects in DNA repair pathways." But will they respond? "So far, scientists have not been able to predict who will benefit from this drug," says Leung. "At the same time, it is equally important to find out which patients are not responding, so as to avoid unneeded treatments — and, more importantly, false hope in patients. Therefore, we urgently need a sensitive tool that is able to distinguish responders from non-responders."

To scientists, these marks are the equivalent of signposts, and "we predict that people who will respond to these drugs will have a distinctive set of protein marks."

With support from the Patrick C. Walsh Prostate Cancer Research Fund, Leung hopes to develop such a tool, along with Hopkins co-investigators Ken Pienta, H. Ballentine Carter, and Robert Cole; and Phillip Sharp, of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology. "As its name implies, a PARP inhibitor stops the PARP enzyme from working," explains Leung. "PARP works by putting a specific mark on proteins. In cancer cells, the abnormal activity of PARP even adds marks to proteins that are normally unmarked." To scientists looking at proteins, such marks are the equivalent of signposts, and "we predict that people who will respond to these drugs will have a distinctive set of protein marks. Thus, the ability to identify these protein marks may likely be the key to predict which patients will respond well to PARP-inhibiting drugs. Recently, our lab published a highly sensitive method to identify such protein marks. We are now geared to apply our method to a panel of prostate cancer cell lines." Some of these cancer cells are killed by PARP inhibitors, and some are not. "Using these data, we will be able to identify which protein marks can distinguish responders from non-responders." Leung hopes this work will identify a biomarker that can be used in a blood test to help determine which men will benefit from PARP-blocking drugs.

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