12:00 AM
May 07, 2015
 |  BC Innovations  |  Product R&D

Degrade and destroy

How GTx's androgen receptor degraders could beat resistance in prostate cancer

GTx Inc. thinks there are lessons about castration-resistant prostate cancer to be learned from breast cancer. The company has licensed a technology from the University of Tennessee Research Foundation that selectively degrades androgen receptors, and is designed to rule out resistance by destroying all forms of the receptor.

The approach has proved successful in hormone-dependent breast cancer. Seragon Pharmaceuticals Inc. developed a series of selective estrogen receptor degraders (SERDs) that bind various forms of the estrogen receptor and tag it for degradation. Seragon was acquired by the Genentech Inc. unit of Roche last year, which now has the lead SERD, ARN-810, in Phase II/III testing for advanced estrogen receptor-positive breast cancer.

Almost all prostate cancers depend on activation of the androgen receptor, a transcription factor that binds androgens such as testosterone and dihydrotestosterone and drives expression of genes involved in prostate tissue growth and survival.

The idea of catalyzing receptor degradation expands the range of strategies developed to interfere with androgen signaling. Various compounds have been developed, or are being explored, that interrupt the synthesis of androgen precursors, androgens themselves or androgen receptors, block binding of androgens to their receptors, or prevent the translocation of receptors to their site of action in the nucleus. (See <div>Figure: Targeting androgen receptor pathways</div>)

First-line treatment for prostate cancer is usually androgen deprivation therapy (ADT) - either by surgical or pharmacological castration - which works by preventing the production of androgens, but is often limited by resistance when the tumor adapts to androgens from other sources. The traditional pharmacological ADT agents - LHRH antagonists or analogs - specifically block a pathway that stimulates testosterone synthesis in the testes. Although that is the primary site for testosterone production, dihydrotestosterone is also produced in the adrenal glands and both hormones can be produced by the tumor itself.

Zytiga abiraterone, marketed by Johnson & Johnson, was developed to address castration-resistant prostate cancer (CRPC) by blocking androgen production from all three sources. In addition, Medivation Inc. and Astellas Pharma Inc. market Xtandi enzalutamide, an antagonist that blocks the ligand binding site on the androgen receptor.

But about 30% of CRPC patients are resistant to both therapies from the outset, and many patients acquire resistance during treatment.

According to Robert Wills, executive chairman of GTx, there is mounting evidence that the non-response to those therapies is thought to be caused by expression of constitutively active androgen receptor splice variants that lack the ligand-binding domain. Those variants drive tumor growth independent of the presence of androgens, he told BioCentury.

The approach taken by University of Tennessee researchers in marking all androgen receptors - full-length and splice variants - for degradation provides a strategy for blocking ligand-independent receptor activation.

Given the data on estrogen...

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