Linked regulation of tumor angiogenesis and chemo-resistance

肿瘤血管生成和化疗耐药的关联调节

基本信息

批准号：
9306421
负责人：
RASHMI S. HEGDE
金额：
$ 35.69万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306421
关键词：
Angiogenesis Inhibition Angiogenesis Inhibitors Antineoplastic Agents Attenuated Biochemical Biochemistry Biology Cell Line Cell Survival Chemicals Chemosensitization Clinical Cysteine DNA DNA Damage DNA Repair Development Dose Drug Design Endothelial Cells Eye Genetic Goals Hypoxia In Vitro KDR gene Knock-in Lead Link Malignant Neoplasms Molecular Molecular Target Mus Neoadjuvant Therapy Neoplasm Metastasis Paracrine Communication Pathologic Neovascularization Pathway interactions Patients Pharmaceutical Chemistry Process Protein Dephosphorylation Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Radiation Reaction Regulation Repair Complex Resistance Resistance development Role Stress Structure Structure-Activity Relationship Testing Tumor Angiogenesis Tyrosine Vascular Endothelial Growth Factors Xenograft Model Xenograft procedure angiogenesis base cancer cell cancer therapy chemosensitizing agent chemotherapy clinical translation drug development effective therapy in vivo inhibitor/antagonist insight interdisciplinary approach mouse model neoplastic cell neovascularization new therapeutic target novel novel strategies phosphatase inhibitor promoter repaired sensor small molecule inhibitor success therapeutic target tool tumor tumor growth tumor xenograft

项目摘要

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.

项目摘要血管生成是癌症的标志之一，也是备受抗衡的治疗靶标。临床用途中的大多数抗血管生成剂靶向VEGF，VEGF受体或相关酪氨酸激酶，并在新辅助背景下显示出巨大的希望。但是，不完全抑制，回避机制，转移增加以及抵抗的发展具有有限的长期成功，强调了对更好地理解血管生成调节的细微差别和鉴定治疗的新目标。最近的证据表明DNA损伤修复（DDR）途径的作用在低氧应激条件下的病理血管生成，如增长时所观察到的肿瘤。 DDR途径也是公认的对DNA抗性的启动子损害癌症治疗，例如化学疗法和放射线。在这里我们提出一个新的分子靶标，眼睛不存在蛋白质酪氨酸磷酸酶（EYA-PTP）类似地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活性促进了DDR和血管生成，并且在宿主内皮细胞中抑制EYA-PTP或缺失显着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，（2）使用现有以及新开发的EYA-PTP抑制剂，作为抗血管生成和化学的抑制剂基于细胞线和患者衍生的俄言异种移植物中的药物。该提案的总体影响是它将定义两者涉及的新途径肿瘤血管生成和对DNA破坏一线疗法的抗性。两者都使用遗传和化学生物学方法我们将证明EYA-PTPS 是可进行的癌症治疗靶标。