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Doubling up on Advanced Prostate Cancer with PARP-1 Inhibitors

10/19/13

Targeting dual roles of PAPR-1 may slow cancer growth and progression, Jefferson's Kimmel Cancer Center researchers say

A newly-discovered function of PARP-1 could be the key to more effective therapeutics to treat advanced prostate cancer patients, a recent, preclinical study published in Cancer Discovery by Jefferson's Kimmel Cancer Center researchers suggests.

The team, led by Karen Knudsen, PhD, Professor in the Department of Cancer Biology at Thomas Jefferson University, found that functions of PARP-1 not only include DNA damage repair but also androgen receptor (AR) regulation in advanced prostate cancer growth and progression. Inhibiting PARP-1 in various models, the researchers found, also suppressed AR activity, which fuels prostate growth.

Researchers believe that the dual function of PARP-1—both AR and DNA damage function—could be leveraged for therapeutic benefit. New PARP-1 inhibitors targeting both could slow down advanced-stage prostate cancer patients and shrink tumors, the team surmises.

"We hope to capitalize on this previously unknown function in PARP-1 in prostate cancer," said Dr. Knudsen. "Our data show that PARP-1 plays a major role in controlling AR function and that, when suppressed with inhibitors, enhanced anti-tumor effects of castration and delayed onset to castration resistance. "

"This is the basis to support a clinical trial investigating new PARP-1 inhibitors in these patients," she added.

Today, PARP-1 is seen as a valuable target because of its involvement in DNA repair for cancer cells. The therapy has been successful when combined with DNA-damaging drugs because it heightens the apoptotic activity of these drugs. In other words, it helps halt tumor growth, but only by stopping DNA repair in various cancers.

Prostate cancer is dependent on AR activity for growth and survival, and is largely resistant to standard chemotherapy. AR-directed therapies are the first-line intervention for patients with advanced disease; however, recurrent tumors arise when AR is reactivated, a common occurrence in the castrate-resistant stage of the disease.

Therefore, there is a dire need to develop means to suppress the AR function in these patients. With this new role defined, newly-designed PARP-1 inhibiters targeting both functions could sensitize prostate cancer, so AR-directed therapies can perform their intended function in these patients, the researchers suggest in the paper.

Almost 40 percent of men with prostate cancer progress into an advanced stage, including castrate-resistant prostate cancer, where chemotherapy and other therapies have little to no effect.

Using various in vitro and in vivo genetically-defined model systems and applying an analysis known as ChIP sequencing, the researchers found that PARP-1 activity is required for AR function and is increased in castrate-resistant prostate cancer. What's more, inhibiting PARP-1 suppressed proliferation of primary human cancer cells.

"These findings introduce a paradigm shift with regard to PARP-1 in prostate cancer," said Dr. Knudsen, "and provide the basis for new therapies that could help a whole population of cancer patients who have little options."

Dr. Knudsen recently received a two-year Challenge Award worth $1 million  from the Prostate Cancer Foundation (PCF) for her work with PARP-1 and prostate cancer, and attended PCF's 10th annual fundraiser in Philadelphia.

This work was supported by NIH grants (R01 CA099996-09, and R01 ES016675-11), the Commonwealth of Pennsylvania grant, a Prostate Cancer Foundation Creativity award, a Prostate Cancer Foundation Young Investigator Award grants from the National Health and Medical Research Council of Australia, a Cancer Council of South Australia Senior Research Fellowship, and Pre-doctoral Fellowships from the DOD.

For more information, contact: Steve Graff, Thomas Jefferson University and Hospitals, 833 Chestnut Street, Suite 1140, Philadelphia, PA 19107, (215) 955-5291, (215) 955-5008 fax, or email stephen.graff@jefferson.edu.