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：
10248475
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10248475
关键词：
Angiogenesis Inhibition Angiogenesis Inhibitors Antineoplastic Agents Attenuated Biochemical Biochemistry Biology Cell Line Cell Survival Chemicals Chemoresistance Chemosensitization Chemotherapy and/or radiation Clinical Cysteine DNA DNA Damage DNA Repair Development Dose Drug Design Endothelial Cells Endothelium 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 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 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.

项目概要血管生成是癌症的标志之一，也是备受追捧的治疗靶点。临床上使用的大多数抗血管生成药物都靶向 VEGF、VEGF 受体或相关药物。酪氨酸激酶，并在新辅助治疗中显示出巨大的前景。然而，不完全抑制、逃避机制、增加的转移以及耐药性的发展限制了长期成功，强调需要更好地了解血管生成调节的细微差别和识别治疗的新目标。最近的证据表明 DNA 损伤修复 (DDR) 途径在缺氧应激条件下的病理性血管生成，如生长中所观察到的 DDR途径也是公认的DNA抗性促进剂。在此我们提出了一种破坏性癌症治疗方法，例如化疗和放疗。新的分子靶点，眼睛缺失蛋白酪氨酸磷酸酶（EYA-PTP）在初步研究中同时针对肿瘤血管生成和化疗耐药。我们已经证明 EYA-PTP 活性可促进 DDR 和血管生成，并且宿主内皮细胞中 EYA-PTP 的抑制或缺失显着减弱在这个项目中，我们计划（1）研究肿瘤生长和血管生成之间的相互作用。宿主内皮 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 EYA-PTP 抑制剂作为抗血管生成和化学增敏作用基于细胞系和患者来源的原位异种移植物的药物。该提案的总体影响在于，它将定义一条涉及两者的新途径肿瘤血管生成，以及对 DNA 损伤一线疗法的抵抗力。我们将通过遗传和化学生物学方法证明 EYA-PTP 是易于处理的癌症治疗靶点。