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