This renewal application will build on our previous studies, in which we established a roles heat shock protein (Hsp) 27 as a stress-induced cytoprotective chaperone that increases after hormone- and chemo- therapy to inhibit treatment-induced cell death. We will explore the hypothesis that Hsp27 is a therapeutic """"""""hyper-node"""""""", a target situated as a 'Hub"""""""" at the center of many pathways regulating the response to cell stress and therapeutic stimuli. Hsp27 forms oligomers during cell stress to prevent aggregation, or becomes phosphorylated to chaperone and regulate activity or degradation of many varied client proteins, including the transcriptional activity of stat-3 and AR.
Aim 1 will elucidate pathways by which Hsp27 regulates CaP cell survival, using bioprofiling and directed functional approaches. Gene and antibody expression profiles of Hsp27 overexpression vs knockdown, coupled to ingenuity pathway analysis, will identify gene networks affected by Hsp27. In parallel, Aim 2 will focus on roles of Hsp27 in 3 pathways linked to HRPC and therapeutic resistance, and specifically test a) whether ligand-independent (androgen depleted) AR activity associated with Al progression is modulated by interactions between IL-6signal transduction, ligand- depleted AR transactivation, and increased Hsp27 activity;b) effects of Hsp27-induced PEA-15 phosphorylation on cell proliferation (by promoting ERK/MAPK activation) and inhibition of Fas mediated cell death, and c) whether treatment induced stress up-regulates the unfolded protein response (DPR) in CaP, and the role of Hsp27 is a downstream effector in endoplasmic reticular (ER) stress.
Aim 3 will evaluate the safety and activity of an Hsp27 antisense inhibitor (OGX-427) in a Phase I/II study in men with mHRPC. The phase I portion will define the pharmacokinetic and toxicity profile of OGX-427 and determine the recommended phase II dose of OGX-427 given as a 2-hour IV infusion once weekly. The phase II portion of this study will then evaluate the anti-cancer activity of OGX-427, assessed primarily by PSA """"""""response"""""""", in part as a pharmacodynamic surrogate of AR inhibition. Correlative studies are also incorporated to evaluate the biologic effectiveness of OGX-427 by analysis of bone marrow aspirates and tissue for Hsp27 and AR protein levels. Collectively, these studies will improve our understanding of role of Hsp27 in adaptive cell survival, treatment resistance, and most importantly, as a new therapeutic target in mHRPC.
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