While androgen deprivation therapy for advanced prostate cancer results in tumor regression, eventually prostate cancer growth resumes in virtually all patients. Relapsed prostate cancer termed “castration resistant” is incurable. Androgen receptor (AR) and its constitutively active variants (such as AR-V7) drive castration resistant prostate cancer (CRPC) progression. We demonstrated that Vav3, a Rho GTPase guanine nucleotide exchange factor, is increased in CRPC and enhances the activity of AR and AR variants. Strikingly, Vav3 is sufficient to confer CRPC tumor growth in vivo. These studies support the therapeutic targeting of Vav3 signaling pathways that cross talk with AR and AR variants.
Our studies on AR variant and Vav3 interaction led to the identification of a new therapeutic target in CRPC, the arginine vasopressin receptor type 1a (AVPR1a).The identification of AVPR1a, a G protein-coupled receptor, in prostate cancer is a novel finding with high potential clinical impact because safe, effective and well-tolerated drugs that inhibit these receptors have already been successfully tested in human clinical trials for non-cancer disorders. The Burnstein lab demonstrated that these AVPR1a inhibitors decrease CRPC growth in mice while exhibiting no toxic side effects. These studies may lead to rapid clinical use of AVPR1a inhibitors in men at risk for, or currently battling, metastatic prostate cancer. In a second major project, we are using an integrated “systems biology” approach to identify additional, novel ways to target constitutively active AR variants in CRPC.
This unbiased and high-throughput methodology utilizes the extensive data available from men with prostate cancer coupled to lab experimental studies designed to discover new proteins that drive the actions of AR variants in prostate cancer. This approach revealed seven proteins that had not previously been linked to constitutive AR variant signaling but that function in interconnecting oncogenic pathways. Expression of these seven proteins is a strong predictor of prostate cancer aggressiveness. The lab has also validated that pharmacologic inhibition of two of these seven interconnected proteins synergistically decreased prostate cancer but not normal prostate cell proliferation. The lab is currently studying how these proteins work in concert to promote prostate cancer and developing combination therapies to block their actions most effectively.
Zhao, N., Peacock, S.O., Lo, C.H., Heidman, L.M., Rice, M.A., Fahrenholtz, C.D., Greene, A.M., Magani, F., Copello, V.A., Martinez, M.J., Zhang, Y., Daaka, Y., Lynch, C.C., Burnstein, K.L. (2019). Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer. Science Translational Medicine: 11(498), eaaw4636. doi:10.1126/scitranslmed.aaw4636
Magani, F., Peacock, S.O., Rice, M.A., Martinez, M.J., Greene, A.M., Magani, P.S., Lyles, R., Weitz, Burnstein, K.L. (2017). Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities. Molecular Cancer Research: MCR, 15(11), 1469–1480. doi:10.1158/1541-7786.MCR-17-0280