Selective androgen receptor degraders show promise as treatment for castration-resistant prostate cancer.
Molecules called selective androgen receptor degraders (SARDs) may offer novel treatment options for patients with advanced prostate cancer, according to a study presented at the 99th meeting of the Endocrine Society.
"If successful in the clinic, the novel highly potent SARDs discovered in this program could be used to treat many of the most aggressive and currently untreatable forms of prostate cancer," said senior study author and principal investigator Ramesh Narayanan, PhD. "The clinical success of new AR [androgen receptor]-targeted therapies in patients with castration-resistant prostate cancer emphasizes the continued importance of the AR signaling axis in the disease.”
The authors reported using a rationale-based drug discovery approach and preclinical models that included cells, xenografts, and patient samples to develop multiple SARDs that degrade all forms of the AR, according to the study.
Their findings suggest that SARDs may provide an effective treatment option for patients with castration-resistant prostate cancer, which is notoriously difficult to treat.
The pharmacology of SARDs allows them to bind, antagonize, and degrade the AR. A benefit of SARDs is that they degrade all forms of AR, including mutants and slice variants (AR-SVs), according to the study. These mechanisms were observed to block the growth of aggressive, treatment-resistant prostate cancers.
"In most cases, the AR promotes the growth of prostate cancer, and currently available AR antagonists do not provide sustained treatment,” Dr Narayanan said. “After a brief period of treatment, the cancer often relapses due to alterations (mutations or splices) in the AR. The altered AR promotes the robust growth of the cancer.”
However, SARDs show promise as a more effective treatment option that would prevent cancer spread compared with current therapies.
"The molecules our group has discovered not only inhibit the AR, but they also degrade the AR and hence may have the potential to provide a more sustained treatment option than a conventional antagonist," Dr Narayanan said.
The investigators said that the AR is challenging to target and degrade through conventional methods.
"Unlike other hormone receptors, the AR is difficult to degrade," Dr Narayanan said. "The SARDs we have developed degrade the AR at pharmacologically achievable concentrations. Moreover, the molecules degrade spliced forms of the AR that do not contain a binding pocket, which was a surprise to the investigators."
In a majority of cases, patients with advanced prostate cancers who relapse from AR antagonists receive chemotherapy. However, it is important to develop novel drugs with mechanisms of action that can provide targeted treatment in order to improve patient outcomes, according to the study.
"Clinical development of these compounds will be initiated later this year," Dr Narayanan concluded.