Developmental Research Pilot Project

Gary Thomas, PhD, Oregon Health & Science University

"Role of PACS-2 in prostate cancer"

Abstract

The long-range goal of this research is to determine the role of the homeostatic regulator PACS-2 in mediating apoptosis in prostate cancer, a leading cause of cancer death in men in the United States. Prostate tumor growth is initially androgen dependent, and androgen ablation is routinely used to treat these cancers. Unfortunately, this treatment frequently fails and the disease recurs as incurable AIPC. The resistance of AIPC to current therapeutics requires new approaches to combat this disease, which will rely on a better understanding of the molecular mechanisms underlying prostate cancer. One gene frequently mutated in prostate cancer is PTEN, which persistently activates the anti-apoptotic Akt signaling pathway. Elevated Akt signaling promotes resistance of many AIPCs to treatment with the death ligand TRAIL, an intensively studied agent for combating a range of cancers due to its selective killing of tumor cells. But how elevated Akt activity confers resistance to TRAIL remains unclear. We recently determined that PACS-2 is required for TRAIL-mediated apoptosis, and that Akt phosphorylation of PACS-2 promotes TRAIL resistance. The goal of this proposal is to test our hypothesis that TRAIL-induced apoptosis in AIPC requires the novel Akt substrate PACS-2, and that dysregulated expression of PACS-2 accelerates prostate tumorigenesis. In Aim 1 we will determine if new generation class I PI3K inhibitors sensitize AIPC to PACS-2-dependent, TRAIL-induced apoptosis. In Aim 2, we will determine the prevalence of PACS-2 misregulation in prostate cancer and whether loss of PACS-2 accelerates the disease in vivo.

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