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

肾细胞癌中靶向 HIF-1α：HDAC 抑制剂的作用

• 批准号: 7688668
• 负责人: Roberto Pili
• 金额: $ 33.68万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-18 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688668
• 关键词: Advanced Malignant Neoplasm; Affect; Angiogenesis Inhibitors; Biological; Blood Vessels; Cancer Center; Cancer Patient; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Data; Development; Endothelial Cells; Epigenetic Process; Evaluation; Failure; Foundations; Future; Gene Proteins; Genes; Genetic; Goals; Growth Factor; HIF1A gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Image; In Vitro; Isoenzymes; Kidney Neoplasms; Malignant Neoplasms; Metastatic Renal Cell Cancer; Microtubules; Modeling; Molecular Target; Pathology; Patients; Pharmacodynamics; Phase; Renal Cell Carcinoma; Renal carcinoma; Research; Research Personnel; Resistance; Role; Sirolimus; Solid Neoplasm; Stream; Testing; Therapeutic; Therapeutic Agents; Transcriptional Regulation; Translating; Tumor Biology; Tyrosine Kinase Inhibitor; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Xenograft Model; angiogenesis; antiangiogenesis therapy; base; bevacizumab; cancer type; chromatin remodeling; design; drug development; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; innovation; insight; interest; kidney cell; novel; novel strategies; novel therapeutics; overexpression; pre-clinical; protein expression; public health relevance; tumor; tumor growth; urologic

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.

描述（由申请人提供）：将染色质重塑作为靶点进行评价导致了重大进展以及生产失败。我们的小组最近提出了组蛋白去乙酰化酶（HDAC）抑制剂作为抗血管生成剂的作用，通过证明它们对转录因子HIF-1 α（HIF-1a）的调节作用。该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肾细胞癌（RCC）。我们的中心假设是：1）靶向HDAC在RCC中显示出临床前和临床活性; 2）HIF-Ia和血管生成受到HDAC抑制剂和RCC中其他靶向疗法的影响;以及3）需要评估HDAC抑制剂的选择性并确定RCC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RCC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雷帕霉素靶点（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与mTOR抑制剂合理联合治疗肾癌的临床研究。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评估体外RCC微环境模型中特异性HDAC同工酶对HIF-1 α和血管生成的调节;具体目标#2确定体内RCC模型中靶向HIF-1 α的新策略与HDAC、微管和mTOR抑制剂的组合的抗肿瘤和抗血管生成活性;具体目的#3评估在RCC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抑制剂对肾细胞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）关于HDAC在肾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，以及3）RCC和晚期癌症患者未来临床试验的基础。公共卫生相关性：我们的研究小组对泌尿系统恶性肿瘤患者的合理联合治疗的发展感兴趣，长期目标是在II-III期临床研究中测试这些组合。该提案具有相关性，因为它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以在治疗肾癌和其他实体瘤的临床试验中进行测试。