Multi-Faceted Targeting of Treatment-Sensitive and Treatment-Resistant Prostate Cancer

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The most common form of prostate cancer, adenocarcinoma, is a major healthcare problem facing Veterans. Prostate cancer is a hormonally driven disease in that it is primarily dependent on androgens for survival and propagation. Androgens provide such survival signals by interacting with androgen receptors (AR) within the prostate cancer cells. Since the testes are the primary source of androgenic steroids, the standard approach to treating advanced prostate cancer is to minimize gonadal production of androgens so as to disrupt androgen/AR signaling. Thus, androgen deprivation therapy (ADT) is the mainstay of treating metastatic disease, and in conjunction with radiation, is also an integral part of treating locally advanced/high risk prostate cancer. Although initially effective, ADT is not curative, and the majority of patients with advanced prostate cancer progress on ADT within a couple of years. Patients who fail ADT are deemed to have castration resistant prostate cancer (CRPC). Such patients may, at least initially, respond to further manipulation of the androgen/AR axis since this signaling pathway is often restored in ADT-failing patients. Hence, considerable efforts have been made to further target this pathway by developing newer generation of androgen biosynthesis and AR inhibitors. This strategy has proven to be beneficial, but again for a limited period of time. The other major treatment for advanced PC is docetaxel- based chemotherapy, which is generally used in men with progressive CRPC. Remarkably, to date, no other agent added to docetaxel has shown to provide better outcomes than single agent docetaxel, which again provides disease control for a limited period of time. Given these challenges, our goal is to use well-defined cell culture models of prostate cancer that encompass a range of disease states to study and interrogate certain ‘nodes’ that integrate specific components of the prostate cancer metabolome. We will target key mediators that regulate and interact with proliferative/anabolic and anti-proliferative/catabolic signals in prostate cancer cells. More specifically, we will study and define interactions between the proliferative erbB-PI3K-Akt-mediated anabolic and the anti-proliferative AMPK- mediated catabolic pathways in AR-expressing and non-AR-expressing prostate cancer cells. For these studies, we will utilize agents that are already in clinical use or in active clinical development, which will facilitate the translation of this work to the clinic if the pre-clinical studies are successful. In other studies, knock down via siRNA or shRNA of some of these key regulatory mediators will provide additional mechanistic insights into the interacting and feedback signals of the prostate cancer metabolome in treatment-sensitive and treatment-resistant prostate cancer cells. We will determine the effects of specific treatments or treatment combinations on the sensitive and resistant prostate cancer cells via metrics that assess drug-drug interactions (synergistic, additive, antagonistic), cell proliferation/growth inhibition, cell cycling and/or cell apoptosis. We will extend some of the studies to SCID-mouse based xenografts to help further define anti-tumor activity and potential treatment-related toxicities in the vivo setting. We believe these combinations of studies, taken together, will have direct clinical relevance, and may help in the development of multi-modal treatments for prostate cancer.