Prostate cancer is the second leading cause of cancer-related death among males in the United States. Beyond the burden in lives affected and lost, more than 192,280 new cases of prostate cancer are projected in 2014. The need to define the genetic basis of this disease is clear. One of the hallmarks of oncogenesis is the aberrant activation of various cellular kinases and growth promoting nuclear hormone receptor signaling. Sustained oncogenic activation requires coordinate inactivation of tumor suppressor genes, such as protein phosphatases, to allow propagation of signaling. Although the inhibition of oncogenic signaling through the development of nuclear hormone antagonists (such as MDV3100) or kinase inhibitors has resulted in some therapeutic success, most exhibit modest efficacy, leading to eventual tumor resistance. The therapeutic activation of tumor suppressor genes has remained largely unexplored. We have developed a series of novel drugs that uniquely target protein phosphatases and possess favorable pharmacokinetics and no significant toxicity. Characterization of these compounds revealed their ability to simultaneously inhibit both the MYC and AR effector pathways in prostate cancer cell lines and mouse models. Our studies represent a first step into that new territory and highlight the potential for the development of small molecule activators of other protein phosphatases and tumor suppressor proteins for the treatment of prostate cancer specifically and other cancers more generally.
Prostate cancer is the second leading cause of cancer-related death among men in the United States. The experiments proposed in this application will focus on developing a novel small molecule series of PP2A activators for the treatment of both castrate resistant and androgen independent prostate cancer. We will use preclinical models of prostate cancer to test the therapeutic potential of targeting this pathway to treat prostate cancer, which might lead to the discovery of new treatment options for this deadly disease.
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