Significant advances as well productive failures have resulted from evaluation of chromatin remodeling as atarget in advanced prostate cancer (PCA). Our group has recently proposed the role of histone deacetylase(HDAC) inhibitors as antiangiogenesis agents for PCA by demonstrating their effect on the modulation thetranscriptional factor HIF-1 alpha (hypoxia inducible factor 1 alpha). The principal objective of the proposedresearch is to further determine the therapeutic potential of targeting HIF-1 alpha and angiogenesis withnovel combination strategies involving HDAC inhibitors for the treatment of PCA. Our central hypotheses arethat 1) targeting HDAC has shown preclinical and clinical activity in PCA; 2) HIF-1 alpha and angiogenesisare affected by HDAC inhibitors and other targeted therapies in PCA; and 3) there is a need to assess theselectivity of HDAC inhibitors and to determine optimal combination strategies in PCA. To this end we willpursue the following goals: 1) to further define the role of specific HDACs in the modulation of HIF-1 alphaand angiogenesis in PCA; 2) to evaluate novel combination strategies using xenograft models with targetedagents such as mTOR and microtubule inhibitors with antiangiogenesis activity likely to be enhanced by useof HDAC inhibitor; and 3) to conduct clinical studies with a rational combination strategy of HDAC and mTORinhibitors in PCA. To achieve our goals we will pursue the following Specific Aims:
Specific Aim #1 Toassess the modulation of HIF-1 alpha and angiogenesis by specific HDAC isozymes in an in vitro PCA bonemicroenvironment model;
Specific Aim #2 To determine the antitumor and antiangiogenesis activity of novelstrategies targeting HIF-1 alpha with combination of HDAC, microtubule and mTOR inhibitors in in vivo PCAmodels;
Specific Aim #3 To assess the biological and clinical activity of an antiangiogenesis combinationstrategy with HDAC and mTOR inhibitors in PCA patients. These studies are significant because theyrepresent the development of rational combinations with HDAC inhibitors by exploiting both theirtranscriptional and non-transcriptional regulation of prostate tumor growth and angiogenesis. We expect thatthese studies will provide 1) new insights on the role of HDACs in prostate tumor microenvironment, 2) earlyclinical evidence that combining HDAC inhibitors and molecular targeted inhibitors increases the antitumoreffects, and 3) the foundation for future clinical trials in PCA patients.
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