Advancing Epidenetic Therapies in Prostate Cancer

研究项目#4 前列腺癌的治疗方法 Roberto皮利，医学博士，Michael A. Carducci，医学博士- 共同主要研究者 染色质重塑作为晚期前列腺癌（PCA）靶点的研究取得了重大进展，但也失败了。我们的小组最近提出了组蛋白去乙酰化酶（HDAC）抑制剂作为PCA的抗血管生成剂的作用，通过证明它们对转录因子HIF-1 α（缺氧诱导因子1 α）的调节作用。拟议研究的主要目的是进一步确定靶向HIF-1 α和血管生成的治疗潜力，采用涉及HDAC抑制剂的新型组合策略治疗PCA。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）HIF-1 α和血管生成受到HDAC抑制剂和PCA中其他靶向治疗的影响; 3）需要评估HDAC抑制剂的选择性并确定PCA中的最佳组合策略。为此，我们将追求以下目标：1）进一步确定特异性HDAC在PCA中调节HIF-1 α和血管生成中的作用; 2）使用具有靶向药物如mTOR和微管抑制剂的异种移植模型评估新的组合策略，所述微管抑制剂具有可能通过使用HDAC抑制剂而增强的抗血管生成活性; HDAC和mTOR抑制剂在PCA中合理联合应用的临床研究。为了实现我们的目标，我们将追求以下具体目标：具体目标#1评估在体外PCA骨微环境模型中通过特定HDAC同工酶对HIF-1 α和血管生成的调节;具体目标#2确定在体内PCA模型中靶向HIF-1 α与HDAC、微管和mTOR抑制剂的组合的新策略的抗肿瘤和抗血管生成活性;具体目的#3评估在PCA患者中使用HDAC和mTOR抑制剂的抗血管生成组合策略的生物学和临床活性。这些研究是重要的，因为它们代表了通过利用HDAC抑制剂对前列腺肿瘤生长和血管生成的转录和非转录调节来开发与HDAC抑制剂的合理组合。我们期望这些研究将提供1）HDAC在前列腺肿瘤微环境中作用的新见解，2）早期临床证据表明HDAC抑制剂和分子靶向抑制剂的组合增加了抗肿瘤作用，3）未来PCA患者临床试验的基础。

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.