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

描述(由申请人提供)：以染色质重塑为目标的评估既有显著的进步，也有生产性的失败。我们的团队最近提出了组蛋白脱乙酰酶(HDAC)抑制剂作为抗血管生成药物的作用，证明了它们对转录因子HIF-1α(HIF-1a)的调节作用。这项研究的主要目的是进一步确定针对HIF-1α和血管生成的新的联合策略，包括HDAC抑制剂，用于治疗肾癌(RCC)。我们的中心假设是：1)靶向HDAC在肾癌中显示出临床前和临床活性；2)在肾癌中，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，并确定在肾癌中的最佳联合策略。为此，我们将追求以下目标：1)进一步确定特定的HDAC在调控HIF-1α和肾癌血管生成中的作用；2)使用靶向药物如哺乳动物靶标雷帕霉素(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RCC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在体外肾癌微环境模型中评估特定HDAC同工酶对HIF-1a和血管生成的调节；特定目标#2在体内肾癌模型中确定针对HIF-1a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评估含有HDAC和mTOR抑制剂的抗血管生成联合策略在肾癌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抑制剂对肾细胞肿瘤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。我们预计，这些研究将提供1)HDAC在肾肿瘤微环境中的作用的新见解，2)早期临床证据表明HDAC抑制剂和分子靶向抑制剂联合使用可增强抗肿瘤效果，3)为未来在肾癌和晚期癌症患者中进行临床试验奠定基础。公共卫生相关性：我们小组对为泌尿系恶性肿瘤患者开发合理的联合疗法感兴趣，长期目标是在II-III期临床研究中测试这些联合疗法。这一建议是相关的，因为这将促进我们对一类新型治疗药物组蛋白脱乙酰酶抑制剂的抗肿瘤作用的了解，并有助于设计合理的组合，用于治疗肾癌和其他实体肿瘤的临床试验。

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.