DCTD Tumor Hypoxia

DCTD肿瘤缺氧

基本信息

批准号：
8429249
负责人：
DAVID HEIMBROOK
金额：
$ 26.18万
依托单位：
LEIDOS BIOMEDICAL RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2018-09-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8429249
关键词：
Achievement Aftercare Angiogenesis Inhibitors Biopsy Cell surface Cells Clinical Clinical Research Colon Carcinoma Colorectal Cancer Development Developmental Therapeutics Program Disseminated Malignant Neoplasm Genetic Hypoxia Journals Laboratories Lead Malignant Neoplasms Mediating Monoclonal Antibodies Oral Administration Pathway interactions Patients Pre-Clinical Model Preclinical Drug Development Production Protocols documentation Publishing Screening procedure Signal Transduction Technology Tissues Topoisomerase II Topotecan Translations United States National Institutes of Health Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Xenograft Model angiogenesis anticancer research autocrine bevacizumab cancer cell cancer diagnosis cancer therapy drug development drug discovery high throughput screening hypoxia inducible factor 1 inhibitor/antagonist metastatic colorectal multicatalytic endopeptidase complex novel therapeutics pre-clinical programs research clinical testing small molecule transcription factor tumor tumor progression tumor xenograft

项目摘要

This project is a major part of the Developmental Therapeutics Program drug discovery and development program within the Division of Cancer Treatment and Diagnosis. The emphasis is on preclinical drug discovery and preclinical drug development. The DTP-Tumor Hypoxia Laboratory (THL) provides support to the Screening Technologies Branch, DTP, DCTD, NCI, in the development of pharmacological and genetic strategies targeting tumor hypoxia and the hypoxia inducible factor 1 (HIF-1) pathway. The main focus of the THL is the discovery and development of novel therapeutic strategies targeting hypoxic cell signaling. Over the last several years, the THL has contributed to the implementation of a targeted screen for the discovery of small molecule inhibitors of HIF-1, a transcription factor involved in angiogenesis and tumor progression. One of the active leads dentified in the high-throughput screen (HTS), topotecan, is currently in clinical testing at the Clinical Research Center, NIH, to evaluate its ability to inhibit HIF-1 alpha expression in patients with metastatic cancer (Protocol NCI 05-C- 0186). Ten patients have been treated and accrual continues. Tissue biopsies taken from patients before treatment and after two cycles of therapy have shown that inhibition of HIF-1 in cancer tissue can be achieved with oral administration of topotecan. This result has led to further studies in preclinical models to explore the combination of topotecan with antiangiogenic agents. In particular, the laboratory has demonstrated that the combination of topotecan with bevacizumab, a monoclonal antibody against VEGF, exerts synergistic antitumor and antiangiogenic activity in tumor xenograft models.

该项目是癌症治疗和诊断分区内开发治疗计划药物发现和开发计划的主要部分。重点是临床前药物发现和临床前药物开发。 DTP肿瘤缺氧实验室（THL）为靶向肿瘤缺氧和缺氧诱导因子1（HIF-1）途径的药理和遗传策略的发展提供了筛查技术分支的支持。 THL的主要重点是针对缺氧细胞信号传导的新型治疗策略的发现和发展。在过去的几年中，THL有助于实施靶向筛选，以发现HIF-1的小分子抑制剂，这是一种参与血管生成和肿瘤进展的转录因子。在NIH的临床研究中心，在高通量屏幕（HTS）（HTS）中牙齿牙齿牙齿牙齿牙齿牙齿牙齿牙齿牙齿牙齿（HTS）（NIH）目前正在临床测试中，以评估其抑制转移性癌症HIF-1 Alpha表达的能力（方案NCI 05-C-0186）。十名患者接受了治疗，并继续进行应计。在治疗前和两个治疗周期后，从患者中获取的组织活检表明，可以通过口服拓扑替康来抑制HIF-1在癌症组织中的抑制作用。该结果导致了临床前模型的进一步研究，以探索拓扑替康与抗血管生成剂的组合。特别是，该实验室表明，拓扑替康与贝伐单抗，一种针对VEGF的单克隆抗体，在肿瘤异种移植模型中发挥协同抗肿瘤和抗血管生成活性。