Advancing Epidenetic Therapies in Prostate Cancer

显着的进展，以及生产失败，导致从评价染色质重塑作为一个 晚期前列腺癌（PCA）的靶点。我们小组最近提出了组蛋白去乙酰化酶的作用 通过证明HDAC抑制剂对PCA的调节作用， 转录因子HIF-1 α（缺氧诱导因子1 α）。建议的主要目标 研究是为了进一步确定靶向HIF-1 α和血管生成的治疗潜力， 涉及HDAC抑制剂用于治疗PCA的新组合策略。我们的主要假设是 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 我们的目标是：1）进一步确定特定HDAC在HIF-1 α调节中的作用 2）使用具有靶向的靶向的异种移植物模型评估新的组合策略， 具有抗血管生成活性的药物如mTOR和微管抑制剂可能通过使用 HDAC和mTOR的合理联合策略进行临床研究 PCA中的抑制剂。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 评估体外PCA骨中特异性HDAC同工酶对HIF-1 α和血管生成的调节 具体目的#2为了确定新的抗肿瘤和抗血管生成活性， 靶向HIF-1 α的策略与HDAC、微管和mTOR抑制剂的组合在体内PCA中 具体目标#3评估抗血管生成组合的生物学和临床活性 在PCA患者中使用HDAC和mTOR抑制剂的策略。这些研究意义重大，因为它们 代表了与HDAC抑制剂的合理组合的开发， 前列腺肿瘤生长和血管生成的转录和非转录调节。我们预计 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活性， 效果，和3）PCA患者的未来临床试验的基础。

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.