New molecules may offer next-generation treatment in prostate cancer

ORLANDO, Fla. — Highly potent selective androgen receptor degraders, or SARDs, may provide advanced treatment options for men with castration-resistant prostate cancer, according to study findings presented here.

Perspective from Alice C. Levine, MD

The novel molecules have a unique pharmacology that enables them to bind, antagonize and degrade the androgen receptor, along with mutants and splice variants, inhibiting the growth of aggressive prostate cancers that are unresponsive to other androgen pathway inhibitors, according to study background.

“These novel molecules are one of the first-in-class potent degraders of the androgen receptor,” Ramesh Narayanan, PhD, associate professor and director of the Center for Cancer Drug Discovery at the University of Tennessee Health Science Center, told Endocrine Today. “These could provide a novel mechanism to target advance prostate cancer that has become refractory to existing treatment options.”

Ramesh Narayanan

Narayanan and colleagues developed a series of SARDs using a rationale-based drug discovery approach and preclinical models that included cells, xenografts and patient-derived samples. Compared with enzalutamide therapy, the researchers found that the SARDs antagonize the androgen receptor with an IC₅₀of ~50-250 nM vs. ~500 nM. The SARDs also degrade full-length androgen receptors in the high nanomolar range (100-500 nM) and variant androgen receptors between 1 and 5 µM. In addition, SARDs inhibit proliferation of full-length androgen receptors and androgen receptor splice variant-dependent PCa cells better than comparators, according to researchers.

Researchers also found that the SARDs inhibited growth of LNCaP androgen-dependent prostate cancer xenograft, the 22RV1 CRPC xenograft and androgen receptor and androgen receptor splice variant-positive CRPC patient-derived xenografts.

In most cases, advanced prostate cancers that relapse from androgen receptor antagonists are treated with chemotherapy; however, for patients who do not respond to androgen receptors or who relapse, it is important to find new drugs that can provide targeted, sustained therapy, Narayanan said.

“If translated in the clinic, these molecules could be used to treat advanced prostate cancer that has become refractory to existing therapies,” Narayanan said in an interview. “Also, prostate cancers that express splice variants could be treated using these molecules.”

“Currently IND-enabling studies are ongoing,” Narayanan said. “If no toxicity is observed, these molecules will likely enter clinical trials by the end of 2017.” – by Regina Schaffer

Reference:

Narayanan, R, et al. OR25-1. Presented at: The Endocrine Society Annual Meeting; April 1-4, 2017; Orlando, Fla.

Disclosures: Narayanan reports consulting for GTx, Inc.

Perspective

Alice C. Levine, MD

Although the majority of bone metastatic prostate cancers will respond initially to androgen ablative therapy, the disease will inevitably progress to a castrate-resistant state. The mechanisms of resistance to hormonal therapy are manifold, including overexpression of androgen receptor (AR) and its coactivators, intratumoral androgen synthesis, and mutations in AR, rendering them either ligand independent or so-called promiscuous (may be activated by other steroid hormones and growth factors). An additional mechanism of castration resistance is the emergent expression of AR splice variants that lack the AR hinge regions and ligand-binding domain. Signalling via AR splice variants is not inhibited by the existing anti-androgens that target the ligand-binding domain of AR.

Investigators at the University of Tennessee, in collaboration with GTX Inc., reported on the development of new compounds that degrade AR protein (SARDs). Their initial aim was to develop new generation SARDs that are more potent than existing androgen receptor antagonists so that intracrine androgens would be prevented from stimulating wild-type (full-length) AR in prostate cancer cells. However, Narayanen and colleagues reported that two novel compounds were found to inhibit both wt and mutant AR, including the splice variants. Further, they determined that both cell growth and AR-stimulated gene expression of the human PCa cell line 22RV1 that expresses high levels of AR splice variant AR-V7 was inhibited by the new SARDs, whereas those parameters are unchanged by the addition of the most potent existing anti-androgen enzalutamide.

Continued efforts at better targeting the AR in metastatic prostate cancer have yielded new therapies for men with advanced disease. Unfortunately, to date, each progressive AR-targeted drug has prolonged life by only a matter of months. The preliminary in vitro results with the new SARDs are promising, but results on tumor growth in vivo are very preliminary. However, if these new drugs are confirmed to be more effective than existing anti-androgens, they will continue to chip away at the mechanisms of resistance and prolong life in men with this devastating disease.

Alice C. Levine, MD

Professor of Medicine and Oncological Sciences, Division of Endocrinology, Metabolism and Bone Disease, Icahn School of Medicine at Mount Sinai

Disclosures: Disclosure: Levine reports no relevant financial disclosures.