New Drug Class May Overcome Resistant Prostate Cancers

A new class of cancer drugs designed to overcome drug resistance may help men with aggressive prostate cancer who stopped responding to conventional treatment.

Hsp90 inhibitors specifically target and inactivate a mechanism that prostate cancer cells frequently use to evade standard treatment effects. The treatment is designed to indirectly attack cancer cells, by destabilizing different proteins required for the growth and survival of cancer.

When multiple cancer signals are destroyed at once, it becomes harder for cancers to avoid treatment.

“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,” said study co-leader Paul Workman. “These drugs can hit cancer harder than those targeting only one protein, and look promising for preventing or overcoming drug resistance.”

A study published in Cancer Research examined the effect of Hsp90 inhibition on human cancer cells that produced AR-V7, the most common androgen receptor variant. The cancer cells were grown in a lab and then injected into mice.

The results of the study showed that Hsp90 inhibition reduced the production of AR-V7 by changing the way messenger RNA molecules that carry the code for AR-V7 are processed.

“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,” Workman said. “It's an exciting discovery which adds a string to the bow of these cancer drugs, and means they could work against prostate cancers that have otherwise stopped responding to treatment.”

Researchers also found that the inhibitor reduced the levels of the normal androgen receptor, as well as the prostate molecules AKT and GR. The Hsp90 inhibitors blocked the production of malfunctioned androgen receptor and therefore stripped the cancer cells of their defenses, stopping them from evading hormone treatment.

Since prostate tumors are reliant on androgens to grow and spread, the study findings suggest that the Hsp90 inhibitors may be effective in treatment-resistant prostate cancers that have started to metastases by blocking androgen receptors.

However, the abnormal forms of the androgen receptor show the ability to be switched on all the time, even without androgen hormone stimulation.

“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. “These drugs are already in clinical trials for several types of cancer, and I am excited that our work suggests they could also benefit men with prostate cancer who have otherwise run out of treatment options.”