A Molecular and In Vivo Investigation of Advanced Prostate Cancer: Deconstructing Ampk Activity and Developing An Improved Mouse Model
Prostate cancer is one of the leading causes of cancer-related death in men. Prostate cancer is dependent on androgen receptor (AR)-mediated pathways, and AR is therefore targeted to treat advanced prostate cancer. Despite an initial response to current AR-targeted therapies, patients invariably relapse, due in large part to the reactivation of AR through a variety of mechanisms. My goal is to identify pathways downstream of AR that can be therapeutically targeted. We and others previously demonstrated that in prostate cancer, calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) is a direct downstream target of AR, and can promote disease progression through the phosphorylation and activation of the 5’ AMP activated protein kinase (AMPK). AMPK is a major regulator of cell homeostasis. While it is well established that AMPK is required for processes like cell growth, development, and stress response, its role in cancer is enigmatic. AMPK can promote both oncogenic and tumor suppressive pathways in different contexts, making it challenging to target for cancer drug development. Interestingly, the α1 and α2 isoforms of the catalytic α subunit of AMPK have been shown to localize to distinct compartments within the cell, and molecular studies indicate that these isoforms have non-redundant functions. Furthermore, subcellular populations of AMPK behave differently in response to stress. Together, these findings suggest that separate populations of AMPK within the cell may behave differently, challenging the dogma of AMPK existing as a single signaling molecule. In the advanced stages of prostate cancer, the cancer spreads to local and distant lymph nodes and other organs. Prostate cancer metastasizes primarily to bone, with up to 90% of men who die of prostate cancer having bone metastases upon autopsy. A major limitation in the study of advanced prostate cancer is a lack of relevant preclinical models of disease progression. Rodents are the most commonly used animal models for studying prostate cancer, and many mouse models have been developed and are widely used in prostate cancer research. However, these models typically fail to recapitulate the full progression of prostate cancer in humans. In fact, there are currently no prostate cancer mouse models that reliably produce bone metastases at a similar rate to human disease. Given this issue, I sought to develop a tractable model of mouse prostate cancer metastasis that consistently metastasizes from the primary site to bone, as it does in human disease.
University of Texas Health Science Center at Houston
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