Men with aggressive prostate cancer that has stopped responding to conventional treatment may potentially benefit from a new class of cancer drugs designed to overcome drug resistance, a new study suggests.
Scientists from the Institute of Cancer Research (ICR) in the UK found that the drugs, called Hsp90 inhibitors, specifically target and inactivate a mechanism commonly used by prostate cancer cells to evade the effects of standard treatment.
The findings provide vital information about the role of Hsp90 in drug-resistant prostate cancers, and open up potential new routes to cancer treatment based on blocking this or related proteins, researchers said.
They found that Hsp90 inhibitors countered the effect of malfunctions in the androgen receptor, which often occur in resistance to hormone treatments.
The findings suggest that Hsp90 inhibitors could be effective in prostate cancers that have become resistant to treatment and started spreading round the body.
Hsp90 inhibitors are among several innovative new types of treatment designed to attack cancer indirectly, by destabilising multiple different proteins required for the growth and survival of cancer cells, researchers said.
By destroying several cancer signals at once, Hsp90 inhibitors are designed to make it hard for cancers to escape the effects of treatment, giving them promise as potential ‘resistance-busting’ drugs, they said.
The new findings showed that on top of their known effects on cancer, Hsp90 inhibition also blocked production of abnormal forms of the androgen receptor, stripping cancer cells of their defences against hormone treatments, researchers said.
Prostate tumours rely on male hormones called androgens to grow and spread, and blocking androgen receptors can be an effective treatment, they said.
However, cancer cells often generate abnormal forms of the androgen receptor that can be switched on all the time without the need for androgen hormone stimulation.
Researchers studied the effect of Hsp90 inhibition on human cancer cells that produced the most common androgen receptor variant, called AR-V7. They grew the cancer cells in the lab and injected them into mice.
They showed that Hsp90 inhibition reduced production of AR-V7 through a new and unexpected mechanism of action – by changing the way that messenger RNA molecules carrying the code for AR-V7 are processed.
Hsp90 inhibition also reduced the levels of the normal androgen receptor, and other important prostate cancer molecules called AKT and GR, researchers said.
“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 Paul Workman from ICR.
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