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

• 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
• 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

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.

项目概要（限30行） 针对血管内皮生长因子受体 (VEGFR) 信号传导的酪氨酸激酶抑制剂 (TKI) 途径已成为肿瘤学中的重要治疗方法，共有九种此类 VEGFR-TKI 具有 近十年来获得批准。尽管疗效显着，VEGFR TKI 仍与 高血压及其他心血管后遗症。目前，对于预测因子和预测因子几乎没有达成共识。 VEGF-TKI 相关高血压的预防和治疗策略。该提案是为了响应 NIH 资助机会公告 (FOA) 鼓励有助于以下方面的协作应用 识别和描述有患癌症治疗相关心血管疾病风险的患者 毒性。以范德比尔特心脏肿瘤学项目为平台，我们组建了一个团队，其目标是 了解 VEGF-TKI 相关高血压的机制并制定精准预防措施 和治疗策略。我们假设 VEGFR 和内皮素-1 (ET-1) 信号传导之间的相互作用 VEGF-TKI 相关高血压的影响高血压和血管功能障碍。在基础研究中，我们 研究 VEGF 信号传导调节 ET-1 转录和表达的机制（目标 1）。在 相关的临床和转化研究，我们将确定内皮素受体拮抗剂对 使用批准药物治疗 VEGF-TKI 高血压（目标 2）。我们解决毒性问题的独特方法 与此类癌症疗法相关的可能对研究出现的心脏问题有影响 与其他癌症疗法相比，特别是当这些疗法与 VEGFR-TKI 联合使用时。