Endocrine Abstracts

The AR pathway accumulates myriad genomic and transcriptomic alterations during progression of prostate cancer to a lethal castration-resistant phenotype. The best characterized alterations are point mutations or amplification of the AR gene. More recently, our group had identified structural rearrangements in the AR gene as a novel class of alterations that occur frequently in castration-resistant prostate cancer (CRPC) tissues. AR gene rearrangements are associated with outlier expression profiles of a diverse set of truncated AR variants (AR-Vs) lacking the canonical ligand binding domain (LBD). AR-Vs expressed in CRPC share a common basic structure consisting of the transcriptionally active NH2-terminal domain (NTD) and DNA binding domain (DBD), but diverge in COOH-terminal amino acid sequence and length. AR-Vs function as constitutively active transcription factors and represent a mechanism of resistance to AR-targeted therapies whereby the growth of prostate cancer cells can remain AR-dependent, yet uncoupled from endocrine regulation. Tumors that have developed this mechanism of resistance are unlikely to respond to successive generations of endocrine therapies. The absence of a LBD presents a formidable challenge for direct inhibition of AR-Vs. However, our work has shown that targeting alternative non-LBD AR domains and/or factors required for AR-V-mediated transcriptional activation may hold promise for inhibiting AR-Vs in advanced prostate cancer.

DOI: 10.1530/endoabs.42.IL13

Biographical details: Scott Dehm completed his PhD in 2003 at the Saskatchewan Cancer Agency at the University of Saskatchewan in Canada with Dr. Keith Bonham. He conducted postdoctoral training at Mayo Clinic with Dr. Donald Tindall from 2003–2008. Scott is currently Associate Professor and Apogee Enterprises Endowed Chair in Cancer Research in the Departments of Laboratory Medicine and Pathology and Urology and the Masonic Cancer Center at the University of Minnesota. His research is currently funded by the Prostate Cancer Foundation, US Department of Defense Research Program, American Cancer Society, and the National Cancer Institute.