Novel mechanisms and predictors of VEGF receptor inhibitor-associated hypertension

VEGF 受体抑制剂相关高血压的新机制和预测因子

基本信息

批准号：
10670742
负责人：
Javid J Moslehi
金额：
$ 64.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670742
关键词：
Academic Medical Centers Address Adverse effects Adverse event Affect Aldosterone Biological Blood Pressure Blood Vessels Cancer Patient Cardiac Cardiovascular system Caring Clinic Clinical Clinical Research Clinical Trials Consensus Data Dose Limiting Endothelial Cells Endothelial Growth Factors Receptor Endothelin Endothelin Receptor Endothelin-1 Endothelium Explosion FDA approved Functional disorder Funding Opportunities Gene Expression Gene Expression Regulation Genetic Genetic Transcription Goals Heart failure Human Hypertension KDR gene Kidney Knowledge Malignant Neoplasms Measures Mediating Oncology Outcome Pathway interactions Patient Care Patients Peptides Pharmaceutical Preparations Placebos Plasma Precision therapeutics Prevention Prevention strategy Rattus Receptor Protein-Tyrosine Kinases Receptor Signaling Renal Blood Flow Renal Cell Carcinoma Research Research Personnel Risk Risk Marker Signal Pathway Signal Transduction Smooth Muscle Myocytes Testing Therapeutic Therapeutic Intervention Thrombosis Toxic effect Treatment-Related Cancer Tyrosine Kinase Inhibitor United States National Institutes of Health Vascular Diseases Vascular Endothelial Growth Factor Receptor-3 Vascular Endothelial Growth Factors Vascular Smooth Muscle Vasoconstrictor Agents Veins antagonist cancer therapy clinical care design epigenome glomerular filtration improved inhibitor inhibitor therapy multidisciplinary novel novel therapeutics oncology program programs receptor response risk prediction risk stratification survivorship translational study treatment strategy

项目摘要

Project Summary (Limit 30 lines) Tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR) signaling pathway have emerged as important therapeutics in oncology with a total of nine such VEGFR-TKI having been approved in the last decade. Despite considerable efficacy, VEGFR TKIs are associated with hypertension and other cardiovascular sequalae. Currently, little consensus exists for predictors as well as for preventive and treatment strategies for VEGF-TKI associated hypertension. This proposal is in response to the NIH Funding opportunity announcements (FOA) that encourages collaborative applications that contribute to the identification and characterization of patients at risk of developing cancer treatment-related cardiovascular toxicity. Using the Vanderbilt cardio-oncology program as a platform, we have assembled a team with the goal of understanding the mechanisms of VEGF-TKI associated hypertension and to develop precision preventive and treatment strategies. We hypothesize that interactions between VEGFR and endothelin-1 (ET-1) signaling impact hypertension and vascular dysfunction in VEGF-TKI associated hypertension. In basic studies, we investigate the mechanism by which VEGF signaling regulates ET-1 transcription and expression (aim 1). In correlative clinical and translational studies, we will determine the impact of endothelin receptor antagonism on VEGF-TKI hypertension using approved drugs (aim 2). Our unique approach addressing the toxicities associated with this class of cancer therapies could have implications for studying cardiac issues that arise from other cancer therapies, especially as these are being combined for use with VEGFR-TKI.

项目摘要（限制30行）靶向血管内皮生长因子受体（VEGFR）信号传导的酪氨酸激酶抑制剂（TKIS）在肿瘤学中，途径已成为重要的疗法，总共有9种这样的VEGFR-TKI 在过去十年中获得批准。尽管功效相当大，但VEGFR TKI与高血压和其他心血管序列。目前，预测因素和 VEGF-TKI相关高血压的预防和治疗策略。该建议是对 NIH资助机会公告（FOA）鼓励协作申请有助于患有癌症治疗相关的心血管风险的患者的鉴定和表征毒性。使用范德比尔特心脏肿瘤计划作为平台，我们已经组建了一个目标了解VEGF-TKI相关的高血压的机制并发展精度预防和治疗策略。我们假设VEGFR和内皮素-1（ET-1）信号之间的相互作用在VEGF-TKI相关的高血压中影响高血压和血管功能障碍。在基础研究中，我们研究VEGF信号调节ET-1转录和表达的机制（AIM 1）。在相关临床和翻译研究，我们将确定内皮素受体拮抗作用对使用批准的药物使用VEGF-TKI高血压（AIM 2）。我们针对毒性的独特方法与这类癌症疗法相关来自其他癌症疗法，尤其是将这些疗法合并为VEGFR-TKI。