Advancing Epidenetic Therapies in Prostate Cancer

研究项目#4 《前列腺癌的遗传治疗进展》 Roberto Pili，M.D.，Michael A.Carducci，M.D.--联合首席调查员 对染色质重塑作为晚期前列腺癌(PCa)靶点的评价既有重大的进展，也有生产性的失败。本课题组最近提出了组蛋白脱乙酰酶(HDAC)抑制剂对转录因子HIF-1α(低氧诱导因子1α)的调节作用，从而证明了组蛋白脱乙酰酶抑制剂作为抗血管生成药物在前列腺癌中的作用。这项研究的主要目的是进一步确定以HIF-1α和血管生成为靶点，以HDAC抑制剂为靶点的新组合策略治疗前列腺癌的治疗潜力。我们的中心假设是：1)靶向HDAC在PCa中显示出临床前和临床活性；2)在PCa中，HIF-1α和血管生成受到HDAC抑制剂和其他靶向治疗的影响；以及3)需要评估HDAC抑制剂的选择性，并确定在PCa中的最佳组合策略。为此，我们将致力于以下目标：1)进一步明确特定的HDAC在调节PCa中HIF-1α和血管生成中的作用；2)使用靶向药物如mTOR和微管抑制剂(其抗血管生成活性可能通过使用HDAC抑制剂而增强)的异种移植模型来评估新的联合策略；以及3)在PCa中进行HDAC和mTOR抑制剂的合理组合策略的临床研究。为了实现我们的目标，我们将追求以下特定目标：特定目标#1在体外PCa骨微环境模型中评估特定HDAC同工酶对HIF-1α和血管生成的调节；特定目标#2在体内PCa模型中确定针对HIF-1α与HDAC、微管和mTOR抑制剂组合的新策略的抗肿瘤和抗血管生成活性；特定目标#3评估结合HDAC和mTOR抑制剂的抗血管生成联合策略在PCa患者中的生物学和临床活性。这些研究意义重大，因为它们通过利用HDAC抑制剂对前列腺癌生长和血管生成的转录和非转录调控，代表了与HDAC抑制剂合理组合的发展。我们期望这些研究将为1)HDAC在前列腺癌微环境中的作用提供新的见解，2)早期临床证据表明HDAC抑制剂和分子靶向抑制剂联合使用可以提高抗肿瘤效果，3)为未来在PCa患者中进行临床试验奠定基础。

Research Project #4 "Advancing Epidenetic Therapies in Prostate Cancer" Roberto Pili, M.D., Michael A. Carducci, M.D. - Co-Principal Investigators Significant advances as well productive failures have resulted from evaluation of chromatin remodeling as a target 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 the transcriptional factor HIF-1 alpha (hypoxia inducible factor 1 alpha). The principal objective of the proposed research is to further determine the therapeutic potential of targeting HIF-1 alpha and angiogenesis with novel combination strategies involving HDAC inhibitors for the treatment of PCA. Our central hypotheses are that 1) targeting HDAC has shown preclinical and clinical activity in PCA; 2) HIF-1 alpha and angiogenesis are affected by HDAC inhibitors and other targeted therapies in PCA; and 3) there is a need to assess the selectivity of HDAC inhibitors and to determine optimal combination strategies in PCA. To this end we will pursue the following goals: 1) to further define the role of specific HDACs in the modulation of HIF-1 alpha and angiogenesis in PCA; 2) to evaluate novel combination strategies using xenograft models with targeted agents such as 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 PCA. To achieve our goals we will pursue the following Specific Aims: Specific Aim #1 To assess the modulation of HIF-1 alpha and angiogenesis by specific HDAC isozymes in an in vitro PCA bone microenvironment model; Specific Aim #2 To determine the antitumor and antiangiogenesis activity of novel strategies targeting HIF-1 alpha with combination of HDAC, microtubule and mTOR inhibitors in in vivo PCA models; Specific Aim #3 To assess the biological and clinical activity of an antiangiogenesis combination strategy with HDAC and mTOR inhibitors in PCA 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 prostate tumor growth and angiogenesis. We expect that these studies will provide 1) new insights on the role of HDACs in prostate 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 PCA patients.