Protein implicated in advanced prostate cancer

January 9, 2013

Researchers at Dana-Farber Cancer Institute, Boston, have discovered a molecular switch that enables advanced prostate cancers to spread without stimulation by male hormones.

Researchers at Dana-Farber Cancer Institute, Boston, have discovered a molecular switch that enables advanced prostate cancers to spread without stimulation by male hormones.

The authors say the finding could lead to a new treatment for castration-resistant prostate cancer (CRPC).

Writing in the journal Science (2012; 338:1465-9), the authors report that the molecular switch occurs in a protein, EZH2, which is increased in CRPC.

EZH2 is part of a protein complex that normally shuts off the expression of genes. But in CRPC cells, "It isn't working the way people had thought," said co-senior author Myles Brown, MD. Instead, EZH2 switches into a different mode, activating cell-growth genes-even in the absence of androgen hormones-that spur the dangerous growth and spread of these cancers.

As a result, the authors suggest that drugs designed to stifle this unexpected function of EZH2 might be effective as a new treatment strategy for CRPC tumors.

Previously, it was found that EZH2 levels are dramatically increased in late-stage castration-resistant prostate cancer, Dr. Brown said, but researchers thought the protein was acting primarily to turn off gene activity, which is its normal role.

Drugs aimed at blocking EZH2 activity are being tested in other cancers, where they are designed to block the protein's gene-suppressing role. However, they carry a risk of harmful side effects as a result.

"But we found that isn't the important function of EZH2 in CRPC," Dr. Brown explained. "In these cancers, EZH2 works with the androgen receptor to turn on genes involved with cell growth." As a result, he proposes that inhibitors of EZH2 that avoid targeting its gene-repressor function might be a safe and effective strategy for use in castration-resistant prostate cancers.

Further, said Dr. Brown, the EZH2 protein itself is activated by a molecular signaling pathway known as PI3K, or PI3 kinase. Several PI3K inhibitors are in clinical trials at present, and Dr. Brown said that a combination of drugs to inhibit both that pathway and the EZH2 protein might be yet another way to attack resistant prostate cancers.