Targeting HIF-1alpha in renal cell carcinoma: the role of HDAC inhibitors

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DESCRIPTION (provided by applicant): Significant advances as well productive failures have resulted from evaluation of chromatin remodeling as a target. Our group has recently proposed the role of histone deacetylase (HDAC) inhibitors as antiangiogenesis agents by demonstrating their effect on the modulation the transcriptional factor HIF-1 alpha (HIF-1a). The principal objective of the proposed research is to further determine the therapeutic potential of targeting HIF-1 a and angiogenesis with novel combination strategies involving HDAC inhibitors for the treatment of renal cell carcinoma (RCC). Our central hypotheses are that 1) targeting HDAC has shown preclinical and clinical activity in RCC; 2) HIF-1 a and angiogenesis are affected by HDAC inhibitors and other targeted therapies in RCC; and 3) there is a need to assess the selectivity of HDAC inhibitors and to determine optimal combination strategies in RCC. To this end we will pursue the following goals: 1) to further define the role of specific HDACs in the modulation of HIF-1 a and angiogenesis in RCC; 2) to evaluate novel combination strategies using xenograft models with targeted agents such as mammalian-target-of-rapamycin (mTOR) and microtubule inhibitors with antiangiogenesis activity likely to be enhanced by use of HDAC inhibitor; and 3) to conduct clinical studies with a rational combination strategy of HDAC and mTOR inhibitors in RCC. To achieve our goals we will pursue the following Specific Aims: Specific Aim #1 To assess the modulation of HIF-1a and angiogenesis by specific HDAC isozymes in an in vitro RCC microenvironment model; Specific Aim #2 To determine the antitumor and antiangiogenesis activity of novel strategies targeting HIF-1 a with combination of HDAC, microtubule and mTOR inhibitors in in vivo RCC models; Specific Aim #3 To assess the biological and clinical activity of an antiangiogenesis combination strategy with HDAC and mTOR inhibitors in RCC patients. These studies are significant because they represent the development of rational combinations with HDAC inhibitors by exploiting both their transcriptional and non-transcriptional regulation of renal cell tumor growth and angiogenesis. We expect that these studies will provide 1) new insights on the role of HDACs in the renal tumor microenvironment, 2) early clinical evidence that combining HDAC inhibitors and molecular targeted inhibitors increases the antitumor effects, and 3) the foundation for future clinical trials in RCC and advanced cancer patients. PUBLIC HEALTH RELEVANCE: Our group is interested in the development of rational combination therapies for patients with urological malignancies with the long-term goal of testing these combinations in phase II-III clinical studies. This proposal is relevant because will advance our understanding of the antitumor effect of a novel class of therapeutic agents, the histone deacetylase inhibitors, and help to design rational combinations to be tested in clinical trials for the treatment of kidney cancer and other solid tumors.