Advancing Epidenetic Therapies in Prostate Cancer

由于对染色质重塑的评估是一种 晚期前列腺癌(PCa)的靶点。我们的小组最近提出了组蛋白脱乙酰酶的作用 (HDAC)抑制剂作为PCa抗血管生成药物的实验研究 转录因子HIF-1α(缺氧诱导因子1α)。建议的主要目标是 研究将进一步确定靶向HIF-1α和血管生成的治疗潜力 使用HDAC抑制剂治疗前列腺癌的新组合策略。我们的中心假设是 1)靶向HDAC在前列腺癌中显示出临床前和临床活性；2)HIF-1α与血管生成 受到HDAC抑制剂和其他靶向治疗的影响；以及3)有必要评估 目的是研究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)进一步确定特定的HDAC在调节HIF-1α中的作用 2)使用靶向的异种移植模型评价新的联合治疗策略。 MTOR和微管抑制剂等具有抗血管生成活性的药物可能通过使用而增强 采用HDAC和mTOR的合理组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至 特异性HDAC同工酶对体外培养的PCa骨中HIF-1α和血管生成的调节作用 微环境模型；特异靶#2测定新化合物的抗肿瘤和抗血管生成活性 联合应用HDAC、微管和mTOR抑制剂靶向HIF-1α的体内PCa研究 模型；评估抗血管生成组合物的生物学和临床活性的特定目标#3 前列腺癌患者应用HDAC和mTOR抑制剂的策略。这些研究具有重要意义，因为它们 代表与HDAC抑制剂的合理组合的发展，通过利用它们的 前列腺癌生长和血管生成的转录和非转录调控。我们期待着 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 HDAC抑制剂和分子靶向抑制剂联合应用可增强抗肿瘤作用的临床证据 效果，以及3)未来在PCa患者中进行临床试验的基础。

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.