Linked regulation of tumor angiogenesis and chemo-resistance

项目摘要 血管生成是癌症的标志之一，也是备受关注的治疗靶点。 临床上使用的大多数抗血管生成剂靶向VEGF、VEGF受体或相关受体。 酪氨酸激酶，并已显示出显着的承诺，在新辅助剂的情况下。 然而，不完全的抑制、逃避机制、增加的转移和 耐药性的发展限制了长期的成功，强调需要 更好地理解血管生成调节的细微差别， 新的治疗目标 最近的证据表明，DNA损伤修复（DDR）途径在 在缺氧应激条件下的病理性血管生成，如在生长中观察到的， 肿瘤的DDR途径也是公认的DNA抗性启动子 有害的癌症治疗，如化疗和放疗。在这里，我们提出一个 新的分子靶点，眼睛缺失蛋白酪氨酸磷酸酶（EYA-PTP）， 同时靶向肿瘤血管生成和化学抗性。在初步研究中 我们已经表明EYA-PTP活性促进DDR和血管生成， 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EYA、肿瘤血管生成和化学抗性，和（2）使用现有 和新开发的EYA-PTP抑制剂作为抗血管生成和化学增敏剂 在基于细胞系的和患者来源的正视异种移植物中的药物。 这一提议的总体影响是，它将确定一条涉及这两个方面的新途径。 肿瘤血管生成和对DNA损伤一线疗法的抗性。同时使用 通过遗传学和化学生物学方法，我们将证明EYA-PTP 是易于控制的癌症治疗靶点。

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.