Public Release:  New target for prostate cancer resistant to anti-hormone therapies

BET bromodomain inhibitors look promising for castration-resistant prostate cancer

University of Michigan Health System

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IMAGE: This is Arul Chinnaiyan, M.D., Ph.D. view more

Credit: University of Michigan Health System

ANN ARBOR, Mich. -- Prostate cancer becomes deadly when anti-hormone treatments stop working. Now a new study suggests a way to block the hormones at their entrance.

Researchers from the University of Michigan Comprehensive Cancer Center have found that a protein called BET bromodomain protein 4 binds to the hormone androgen receptor downstream of where current therapies work - targeting androgen receptor signaling.

This could mean that when prostate cancer becomes resistant to current treatments, it might remain sensitive to a drug that targets BET bromodomain proteins. Results appear in Nature.

"We think we can target prostate cancer through androgen receptor signaling, rather than directly hitting the androgen receptor. These initial findings suggest the potential that a BET bromodomain inhibitor can work even when prostate cancer becomes resistant to anti-hormone therapies," says senior study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at the University of Michigan Medical School.

The researchers used a compound called JQ1, designed to inhibit BET bromodomain proteins, to test the concept in cell lines and mice. They found that JQ1 blocked androgen signaling even when cells no longer responded to current anti-androgen therapies. The JQ1 BET bromodomain inhibitor blocked androgen receptor signaling, which is downstream of the androgen receptor, making it potentially unaffected by the acquired resistance related to hormone signaling.

The researchers also found that BET inhibitors appear to block several transcription factors, including the TMPRSS2-ERG gene fusion and MYC, known to drive prostate cancer.

Bromodomain inhibitors have been explored in blood cancers and a rare cancer called NUT midline carcinoma. This is one of the first indications that BET bromodomain inhibitors may be beneficial in a common solid tumor.

A newly formed company, OncoFusion Therapeutics, co-founded by Chinnaiyan and study co-author Shaomeng Wang, Ph.D., will look at developing potential BET bromodomain inhibitors to attack prostate cancer.

"BET bromodomain represents one of the most exciting targets in epigenetics," Chinnaiyan says. "Developing new ways to treat castration-resistant prostate cancer is critical to improving survival for this disease."

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Additional authors: Irfan A. Asangani, Vijaya L. Dommeti, Xiaoju Wang, Rohit Malik, Marcin Cieslik, June Escara-Wilke, Kari Wilder-Romans, Sudheer Dhanireddy, Carl Engelke, Mathew K. Iyer, Xiaojun Jing, Yi-Mi Wu, Xuhong Cao, Felix Y. Feng, from U-M; Rendong Yang and Zhaohui S. Qin, from Emory University

Funding: Prostate Cancer Foundation, National Cancer Institute grants CA111275 and CA69568, Doris Duke Charitable Foundation, American Cancer Society, A. Alfred Taubman Institute

Disclosure: Chinnaiyan and Wang are co-founders of OncoFusion Therapeutics, which is developing novel BET bromodomain inhibitors. Chinnaiyan, Wang and the University of Michigan have equity interest in OncoFusion.

Reference: Nature, DOI: 10.1038/nature13229, published online April 23, 2014

Resources:
U-M Cancer AnswerLine, 800-865-1125
U-M Comprehensive Cancer Center, http://www.mcancer.org
Clinical trials at U-M, http://www.mcancer.org/clinicaltrials
mCancerTalk blog, http://uofmhealthblogs.org/cancer

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