A new class of cancer drugs—Hsp90 inhibitors—could provide effective therapy for advanced prostate cancers that have become resistant to hormone treatment, according to a study published May 1, 2016 in the journal Cancer Research.
Because prostate tumors rely on androgens to grow and spread, depriving androgen receptors of these hormones can be an effective treatment. However, cancer cells eventually generate variants of the androgen receptors that can function continuously without the need for androgen stimulation.
For this study, researchers targeted the most common one of these androgen receptor variants, AR-V7. They grew the cancer cells in the lab and injected them into mice. Then they administered a drug (onalespib) that inhibits Hsp90, a chaperone molecule involved in the transcriptional activity of these receptors.
“We have demonstrated for the first time that Hsp90 inhibitors can block the production of the most common abnormal androgen receptors that cause many prostate cancers to stop responding to current treatments,” said study co-leader Johann de Bono, MD, PhD, MSc, Professor of Experimental Cancer Medicine at the Institute of Cancer Research (ICR), in London, United Kingdom.
The researchers showed that inhibiting Hsp90 reduced the production of AR-V7, but not by interrupting its known chaperone function. Instead, it occurred through a new and unexpected mechanism of action—by disrupting mRNA splicing of the androgen receptor variant.
“Our study has found that Hsp90 inhibition can specifically stop resistance to hormone treatments in prostate cancer through a completely new mechanism of action involving the processing of messenger RNA,” said study co-leader Paul Workman, PhD, Chief Executive of the ICR.
Inhibiting Hsp90 also reduced the levels of the normal androgen receptor and other important prostate cancer molecules, AKT and GR, the researchers found.
“We call Hsp90 inhibitors ‘network drugs’ because they tackle several of the signals that are hijacked in cancer all at once, across a network rather than just a single signaling pathway,” Dr. Workman said. “These drugs can hit cancer harder than those targeting only one protein, and look promising for preventing or overcoming drug resistance.”
Hsp90 inhibitors are already in clinical trials for several types of cancer, the researchers noted.
“I am excited that our work suggests [these drugs] could also benefit men with prostate cancer who have otherwise run out of treatment options,” Dr. de Bono said.