Linked regulation of tumor angiogenesis and chemo-resistance

项目摘要 血管生成是癌症的标志之一，也是一个备受追捧的治疗靶点。 大多数抗血管生成药物在临床上用于靶向血管内皮生长因子、血管内皮生长因子受体或相关 酪氨酸激酶，并在新佐剂的背景下显示出重大的前景。 然而，不完全抑制、逃避机制、转移增加以及 抗药性的发展限制了长期的成功，突显出需要 更好地理解血管生成调节的细微差别和识别 治疗的新靶点。 最近的证据表明，DNA损伤修复(DDR)途径在 低氧应激条件下的病理性血管生成，如生长发育过程中观察到的 肿瘤。DDR途径也是公认的DNA抗性启动子 破坏性的癌症治疗，如化疗和放射治疗。在这里，我们提出一种 新的分子靶点，眼睛缺失蛋白酪氨酸磷酸酶(EYA-PTP)以 同时靶向肿瘤血管生成和化疗耐药。在初步研究中 我们已经证明，EYA-PTP活性促进DDR和血管生成，并且 抑制宿主内皮细胞中的EYA-PTP或缺失显著减弱 肿瘤生长和血管生成。在这个项目中，我们计划(1)研究 宿主内皮细胞EYA、肿瘤血管生成和化疗耐药性，以及(2)使用现有的 以及新开发的抗血管生成和化学敏感的EYA-PTP抑制剂 基于细胞系的和患者来源的异种异种移植中的药物。 这项提议的总体影响是，它将定义一条涉及这两个领域的新途径 肿瘤血管生成，以及对DNA损伤一线治疗的抵抗力。两者都使用 遗传和化学生物学方法我们将已经证明了EYA-PTPs 是易于治疗的癌症治疗目标。

Project Summary Angiogenesis is one of the hallmarks of cancer and a much-pursued therapeutic target. Most anti-angiogenic agents in clinical use target VEGF, VEGF receptors, or related tyrosine kinases, and have shown significant promise in the neoadjuvant context. However incomplete inhibition, evasive mechanisms, increased metastasis, and the development of resistance have limited long-term success, underscoring the need for a better understanding of the nuances of angiogenic regulation and the identification of new targets for therapy. Recent evidence points to a role for the DNA Damage Repair (DDR) pathway in pathological angiogenesis under conditions of hypoxic stress, as is observed in growing tumors. The DDR pathway is also a recognized promoter of resistance to DNA damaging cancer treatment such as chemotherapy and radiation. Here we propose a novel molecular target, the Eyes Absent protein tyrosine phosphatase (EYA-PTP) to simultaneously target tumor angiogenesis and chemo-resistance. In preliminary studies we have shown that the EYA-PTP activity promotes DDR and angiogenesis, and that inhibition of the EYA-PTP or deletion in host endothelial cells signficantly attenuates tumor growth and angiogenesis. In this project we plan to (1) study the interplay between host endothelial EYA, tumor angiogenesis, and chemo-resistance, and (2) use existing and newly developed EYA-PTP inhibitors as anti-angiogenic and chemosensitzation agents in cell–line based and patient-derived orthoptoic xenografts. The overall impact of this proposal is that it will define a new pathway involved in both tumor angiogenesis, and resistance to DNA damaging first-line therapies. Using both genetic and chemical biology approaches we will have demonstrated that the EYA-PTPs are tractable cancer therapeutic targets.