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

描述(申请人提供)：美国每年有近10,000人发生软组织肉瘤，约40%的患者死于局部疾病或远处转移。随着肉瘤和其他实体肿瘤的生长超过了它们的血液供应，低氧(或缺氧)稳定了低氧诱导因子1a和2a(HIF)，它们与Arnt(又名)结合。HIF-1)，并驱动150多个基因的表达。这些基因调控多种肿瘤表型，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HIFs调控的基因之一，也是推动肿瘤血管生成的重要因素之一。HIF和VEGF在人类肉瘤中高表达，且这些因子水平的升高与疾病的严重程度和转移有关。高强度聚焦因子和血管内皮生长因子也可能参与肿瘤对放射治疗的抵抗。大量的临床前研究发现，抗血管内皮生长因子治疗可以增强放射治疗的效果，这种协同作用在新辅助贝伐单抗(一种抗血管内皮生长因子抗体)和放射治疗肉瘤的II期临床试验中得到证实。这项建议的长期目标是扩大针对VEGF和HIFs的药物在肉瘤患者中的使用，以减少局部复发和远处转移。因此，这项建议旨在验证HIFs和VEGF在调节肉瘤进展、转移和辐射敏感性方面发挥关键和相互依赖的作用的假设。为了验证这一假设，本研究计划将(1)确定HIF在肉瘤发生和转移中的作用，(2)确定血管内皮生长因子抑制对HIF活性、肿瘤侵袭和转移的影响，以及(3)确定HIF和血管内皮生长因子抑制对肉瘤放射反应的影响。这项建议的方法包括肉瘤细胞系和原代内皮细胞的体外分析，基因工程小鼠模型的分析，以及肉瘤患者肿瘤组织样本的分析。

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.