Novel mechanisms and predictors of VEGF receptor inhibitor-associated hypertension

项目摘要（限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（TKI） VEGFR-TKI通路已经成为肿瘤学中的重要治疗剂，总共有九种这样的VEGFR-TKI， 在过去的十年里被批准。尽管有相当大的疗效，但VEGFR TKI与 高血压和其他心血管后遗症。目前，对于预测因子以及 VEGF-TKI相关高血压的预防和治疗策略。这项建议是为了回应 NIH资助机会公告（FOA），鼓励有助于 识别和表征有发生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，目标是 了解VEGF-TKI相关高血压的机制，并制定精确的预防措施， 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 影响VEGF-TKI相关高血压患者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（目的1）。在 通过相关的临床和转化研究，我们将确定内皮素受体拮抗剂对 使用获批药物治疗VEGF-TKI高血压（目的2）。我们独特的解决毒性的方法 与这类癌症治疗相关的研究可能对研究心脏问题产生影响， 从其他癌症治疗，特别是因为这些正在与VEGFR-TKI组合使用。

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.