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Advancing Epidenetic Therapies in Prostate Cancer

推进前列腺癌的流行病治疗

基本信息

批准号：
8719552
负责人：
Roberto Pili
金额：
$ 13.76万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8719552
关键词：
Affect Angiogenesis Inhibitors Biological Blood Vessels Cancer Center Cancer Patient Clinical Clinical Research Clinical Trials Combined Modality Therapy DNA Methyltransferase DNA Modification Methylases Data Development Disease Endothelial Cells Evaluation Failure Foundations Future Goals Growth Factor HIF1A gene Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition In Vitro Isoenzymes Isotretinoin Laboratory Study MS-275 Malignant neoplasm of prostate Metastatic Renal Cell Cancer Microtubules Modeling Molecular Target Pathology Patients Pharmacodynamics Phase Phase II Clinical Trials Prostatic Neoplasms Regulation Research Research Personnel Role Signal Transduction Pathway Testing Therapeutic Transcriptional Regulation Translating Tumor Angiogenesis Tumor Biology Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Xenograft Model angiogenesis antiangiogenesis therapy base bone cancer type chromatin remodeling design drug development human FRAP1 protein hypoxia inducible factor 1 in vivo inhibitor/antagonist innovation insight mTOR Inhibitor men novel novel strategies novel therapeutics phase 1 study pre-clinical prostate cancer model tumor growth tumor microenvironment

项目摘要

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.

染色质重塑作为一种遗传机制的评估取得了重大进展，同时也导致了生产失败