HIFs and VEGF in sarcoma progression, metastasis, and radiation response

HIF 和 VEGF 在肉瘤进展、转移和放射反应中的作用

基本信息

批准号：
8086285
负责人：
M. CELESTE SIMON
金额：
$ 33.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-13 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8086285
关键词：
ARNT gene Affect Antibodies Apoptosis Automobile Driving Binding Biological Blood Vessels Cell Line Cell Proliferation Clinical Complex DNA Development Disease Distant Metastasis Dose Doxorubicin Endothelial Cells Gene Targeting Genes Genetic Transcription Genetically Engineered Mouse Growth Factor Inhibition Human Hypoxia Hypoxia Inducible Factor In Vitro Limb structure Malignant Neoplasms Mediating Methods Modeling Molecular Mus Neoadjuvant Therapy Neoplasm Metastasis Neoplasms in Vascular Tissue Oxygen Pathway interactions Patients Persons Pharmaceutical Preparations Phase II Clinical Trials Phenotype Play Proteins Radiation Radiation Tolerance Radiation therapy Recurrence Regional Disease Research Proposals Resistance Role Solid Neoplasm Staging Testing Therapeutic Tissue Sample Treatment Efficacy Tumor Angiogenesis Tumor Cell Invasion Tumor Tissue United States Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Vascular blood supply Xenograft procedure base bevacizumab cytotoxicity deprivation design hypoxia inducible factor 1 lung sarcoma meetings migration mouse model overexpression preclinical study prevent radiation effect radiation resistance response sarcoma soft tissue tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Soft tissue sarcomas arise in nearly 10,000 persons in the United States each year, and about 40% of patients die of either loco-regional disease or distant metastasis. As sarcomas and other solid tumors outgrow their blood supply, hypoxia (or oxygen deprivation) stabilizes hypoxia inducible factors 1a and 2a (HIFs), which bind to ARNT (a.k.a. HIF-¿) and drive the expression of over 150 genes. These genes regulate) a variety of tumor phenotypes including tumor angiogenesis (or new blood vessel formation), invasion, and metastasis. Vascular endothelial growth factor (VEGF) is one of the genes controlled by HIFs and is also one of the most important factors driving tumor angiogenesis. HIFs and VEGF are overexpressed in human sarcomas, and increasing levels of these factors correlate with extent of disease and metastasis. HIFs and VEGF may also contribute to tumor resistance to radiation therapy. Numerous preclinical studies have found that anti-VEGF therapies can augment the effects of radiation therapy, and this synergistic effect was confirmed in a phase II clinical trial of neoadjuvant bevacizumab (an anti-VEGF antibody) and radiation therapy for sarcomas. The long-term objective of this proposal is to expand the use of agents targeting VEGF and HIFs in patients with sarcoma to reduce loco-regional recurrence and distant metastasis. Consequently, this proposal is designed to test the hypothesis that HIFs and VEGF play critical and interdependent roles in regulating sarcoma progression, metastasis, and radiation sensitivity. To test this hypothesis, this research proposal will (1) determine the role of HIFs in sarcomagenesis and metastasis, (2) determine the effects of VEGF inhibition on HIF activity, tumor invasion, and metastasis, and (3) determine the effects of HIF and VEGF inhibition on response of sarcomas to radiation. The methods of this proposal include analysis of sarcoma cell lines and primary endothelial cells in vitro, analysis of genetically engineered mouse models, and analysis of tumor tissue samples from sarcoma patients. PUBLIC HEALTH RELEVANCE: Oxygen is essential for tumor growth, and tumors must correct oxygen deprivation in order to expand and metastasize. In sarcomas, hypoxia (or low oxygen) stabilizes hypoxia inducible factors 1a and 2a (HIFs) which in turn upregulate (1) vascular endothelial growth factor (VEGF) which induces the formation of new tumor blood vessels and (2) other HIF-target genes which mediate tumor invasion and metastasis. This project will examine the critical and interdependent roles of HIFs and VEGF in sarcoma formation, progression, metastasis, and radiation sensitivity, and identify therapeutic means of targeting these pathways in patients with sarcoma.

描述（由申请人提供）：在美国，每年有近 10,000 人患有软组织肉瘤，大约 40% 的患者死于局部疾病或远处转移，因为肉瘤和其他实体瘤生长超过了血液供应。缺氧（或缺氧）可稳定与 ARNT 结合的缺氧诱导因子 1a 和 2a (HIF) （又名 HIF-¿）并驱动超过 150 个基因的表达，这些基因调节多种肿瘤表型，包括肿瘤血管生成（或新血管形成）、侵袭和转移，血管内皮生长因子 (VEGF) 是其中之一。 HIF 控制的基因也是驱动肿瘤血管生成的最重要因素之一，HIF 和 VEGF 在人类肉瘤中过度表达，并且这些因子的水平增加相关。大量临床前研究发现，抗 VEGF 疗法可以增强放射治疗的效果，并且这种协同作用在 II 期临床试验中得到了证实。新辅助贝伐珠单抗（一种抗 VEGF 抗体）和放射治疗肉瘤该提案的长期目标是扩大针对 VEGF 和 HIF 的药物在患有肉瘤的患者中的使用。经测试，该研究计划旨在检验 HIF 和 VEGF 在调节肉瘤进展、转移和放射敏感性中发挥关键且相互依赖的作用的假设。 (1) 确定 HIF 在肉瘤发生和转移中的作用，(2) 确定 VEGF 抑制对 HIF 活性、肿瘤侵袭和转移的影响，(3) 确定HIF 和 VEGF 抑制对肉瘤放射反应的影响该提案的方法包括体外肉瘤细胞系和原代内皮细胞分析、基因工程小鼠模型分析以及肉瘤患者肿瘤组织样本分析。公共卫生相关性：氧气对于肿瘤生长至关重要，肿瘤必须纠正缺氧才能扩大和转移。在肉瘤中，缺氧（或低氧）可稳定缺氧诱导因子 1a 和 2a (HIF)，进而上调 (1)。诱导新肿瘤血管形成的血管内皮生长因子 (VEGF) 和 (2) 介导肿瘤的其他 HIF 靶基因该项目将研究 HIF 和 VEGF 在肉瘤形成、进展、转移和放射敏感性中的关键和相互依赖的作用，并确定针对肉瘤患者的这些途径的治疗方法。