Genetic & Metabolic Dissection of the CaMKKbeta Signaling Axis in Prostate Cancer

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DESCRIPTION (provided by applicant): While it is known that aberrant androgen receptor (AR) signaling is important for the development of prostate cancer, it has also become evident that AR signaling remains active and necessary in the deadly advanced stages of the disease. Despite the known importance of AR signaling in prostate cancer, the processes downstream of the receptor that drive disease progression remain poorly understood. This knowledge gap has precluded the development of novel therapies, particularly for the advanced stages of the disease for which there is currently no cure. Thus, the long-term goal is to develop new therapeutic approaches for the treatment of prostate cancer. Previous work from several independent laboratories has suggested AR signaling promotes prostate cancer growth, migration, invasion and altered metabolism in part through a Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKKβAMP-activated protein kinase (AMPK) signaling pathway. The primary goal of this proposal is to use a combination of in vitro and in vivo models to define the specific role(s) of AR-mediated CaMKKβ signaling in prostate cancer and test whether it represents a viable drug target in preclinical genetic animal models. The central hypothesis is that the CaMKKβ axis promotes both glucose and fatty acid pathological metabolism and therefore represents a novel target for advanced prostate cancer therapy. This hypothesis is based on the preliminary and published data generated from the applicant's laboratory and is strongly supported by studies from other groups. The hypothesis will be tested with the following two specific aims: Aim 1: Determine the role of ARmediated CaMKKβ-AMPK signaling in prostate cancer cellular metabolism. Aim 2: Genetic dissection of the pathogenic role of CaMKKβ using preclinical mouse models of prostate cancer. Under the first aim, isolated cellular models of prostate cancer will be used to define the specific roles of CaMKKβ, AMPK and candidate downstream signaling targets in pathological metabolism using metabolic flux analysis and comprehensive metabolomic profiling techniques. In the second aim, a combination of genetic mouse models will be used to delineate the role of CaMKKβ in various stages of cancer progression. Further, tumors derived from these studies will be subjected to the metabolomic profiling described in the previous aim. The research is innovative because it tests the novel paradigm that AR signaling promotes prostate cancer progression through the promiscuous metabolism of both sugars and fats. Further, it tests this paradigm using mass spectroscopic techniques that, due to their enhanced resolution, will yield a comprehensive examination of the tumor metabolome. These studies are significant because they will conclusively determine whether CaMKKβ signaling is a viable therapeutic target in vivo and also identify potential metabolic biomarkers of its activity. Ultimately, it is anticipated that the completion of the proposed studis will set the foundation needed for subsequent drug discovery efforts.