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Overcoming the resistance to anti-angiogenesis therapy

克服抗血管生成治疗的耐药性

基本信息

批准号：
8814348
负责人：
Nader Rahimi
金额：
$ 21.36万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-08 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8814348
关键词：
Adjuvant Adverse effects Angiogenesis Inhibitors Antibodies Antineoplastic Agents Biopsy Specimen Boston Cell Culture Techniques Cells Clinical Colorectal Cancer Data Development Dose Endothelial Cells Event FDA approved Goals Human Hypoxia Investigation Lead Ligands Link Lysine Malignant Neoplasms Mediating Medical center Methylation Modeling Molecular Mus Neoplasm Metastasis Patients Pharmaceutical Preparations Phosphotransferases Post-Translational Protein Processing Publications Publishing Research Resistance Resistance development Retrospective Studies Role Science Signal Pathway Signal Transduction Testing Therapeutic Time Tumor Angiogenesis Tyrosine Phosphorylation Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Work Zebrafish angiogenesis antiangiogenesis therapy base cancer therapy clinically relevant colon cancer patients improved inhibitor/antagonist innovation methylation testing mutant novel novel strategies pre-clinical prevent public health relevance resistance mechanism therapeutic angiogenesis tumor tumor growth tumor progression web site

项目摘要

DESCRIPTION (provided by applicant): Anti-angiogenesis therapy has benefited many patients with cancer; however, insufficient efficacy, intrinsic refractoriness, and development of resistance have significantly reduced the therapeutic benefits of these therapies. Various hypotheses were proposed to explain the resistance associated with the anti-angiogenesis therapies, none was proven adequately to explain the apparent refractoriness and development of resistance. There is also a major gap in our understanding of the molecular determinants of development of resistance and refractoriness to anti- angiogenesis agents. Given that a significant research and financial efforts were spent on the development of anti- angiogenesis drugs, understanding the modes and mechanisms of resistance to anti-angiogenesis warrants further investigation. We have recently identified lysine methylation, a novel and previously unrecognized posttranslational modification that promotes kinase activation of VEGFR-2. Preventing methylation of VEGFR-2 on a specific lysine 1041 (K1041) residue inhibited VEGFR-2 mediated angiogenesis in cell culture, zebrafish and tumor growth in mouse. Our preliminary data demonstrates that the methylation of VEGFR-2 is associated with refractoriness and development of resistance to certain cancer therapies. Based on our recent published and data presented in the current application, we propose to investigate role of methylation of VEGFR-2 in de novo resistance to anti- angiogenesis therapy. The following specific aims are proposed to test our hypothesis. (A) Examine the hypothesis that methylation of VEGFR-2 is responsible for refractoriness and development of resistance to certain cancer therapies. Various mouse and zebrafish models will be used to examine role of methylation of VEGFR-2 resistance to anti-angiogenesis therapies. (B)Determine methylation status of VEGFR-2 in human colorectal cancer and correlate with responsiveness to angiogenesis inhibitors. There is an unmet need for effective anti-angiogenesis therapies. Establishing a link between methylation of VEGFR-2 and resistance/refractoriness to anti-angiogenic therapies could lead to a new class of cancer therapy and could overcome refractoriness and resistance to angiogenesis therapies.

描述（由申请人提供）：抗血管生成治疗已使许多癌症患者受益;然而，疗效不足、内在难治性和耐药性的产生显著降低了这些治疗的治疗获益。提出了各种假设来解释与抗血管生成治疗相关的耐药性，但没有一种被证明足以解释明显的难治性和耐药性的发展。在我们对抗血管生成药物产生耐药性和难治性的分子决定因素的理解方面也存在重大差距。鉴于大量的研究和财政努力花费在抗血管生成药物的开发上，了解对抗血管生成的抗性的模式和机制需要进一步研究。我们最近发现了赖氨酸甲基化，一种新的和以前未被识别的翻译后修饰，促进VEGFR-2的激酶激活。阻止VEGFR-2在特定赖氨酸1041（K1041）残基上的甲基化抑制细胞培养物、斑马鱼和小鼠肿瘤生长中VEGFR-2介导的血管生成。我们的初步数据表明，VEGFR-2的甲基化与某些癌症治疗的难治性和耐药性的发展有关。基于我们最近发表的文章和本申请中提供的数据，我们提出研究VEGFR-2甲基化在抗血管生成疗法的从头抗性中的作用。提出以下具体目标来检验我们的假设。(A)检查VEGFR-2甲基化是导致某些癌症治疗的难治性和耐药性发展的假设。将使用各种小鼠和斑马鱼模型来检查VEGFR-2的甲基化对抗血管生成疗法的抗性的作用。（B）测定人结肠直肠癌中VEGFR-2的甲基化状态并与对血管生成抑制剂的反应性相关。对于有效的抗血管生成疗法存在未满足的需求。建立VEGFR-2的甲基化与抗血管生成疗法的抗性/难治性之间的联系可能会导致一类新的癌症疗法，并可能克服对血管生成疗法的难治性和抗性。