Characterization of TRPC6 to predict and prevent chemotherapy-related heart failure

项目摘要/摘要 化疗相关的心脏毒性导致心力衰竭是乳腺癌治疗中的一个主要问题 以及淋巴瘤患者，他们患心力衰竭的可能性是对照组的三倍。累积剂量 蒽环类化疗药物阿霉素与心力衰竭风险的增加密切相关，如 患者被限制在终生累积剂量，即使仍然需要治疗。阿霉素是 通常用于治疗淋巴瘤和高危乳腺癌(三阴性和HER2+乳腺癌) 癌症)。对于HER2+患者，阿霉素与HER2靶向治疗曲妥珠单抗联合使用 这也增加了心脏毒性的风险。不幸的是，预测哪些癌症患者有患癌症的风险 心力衰竭很差，目前的心脏保护疗法有限。我们发表的基因研究已经 发现TRPC6是阿霉素所致心力衰竭的危险基因。我们对IPSC衍生产品的研究 心肌细胞和阿霉素诱导的心肌病小鼠模型显示治疗抑制 TRPC6和TRPC6基因敲除对阿霉素诱导的心脏毒性具有保护作用。我们的预赛 研究和其他研究表明，抑制TRPC6也可能具有抗肿瘤的特性。整体而言 这个项目的科学前提是，增加TRPC6表达或导致获得- 功能与阿霉素相关的心力衰竭有关，TRPC6抑制剂的特征将 改善对需要化疗的患者的护理。为了进一步研究TRPC6在阿霉素中的作用- 相关心力衰竭，并测试TRPC6抑制与阿霉素联合治疗的疗效 将：1.检测TRPC6和其他已知风险基因在多个、大的、特征良好的疾病中的遗传关联 淋巴瘤和乳腺癌患者的样本。2.在体外确定哪些变异导致功能增益 以及哪些抑制剂可以阻止这种功能的获得。3.评价TRPC6的疗效和心脏保护作用 类似于三阴性乳腺癌的致瘤小鼠模型中的抑制物。

PROJECT SUMMARY/ABSTRACT Chemotherapy-related cardiotoxicity leading to heart failure is a major issue in the treatment of breast cancer and lymphoma patients, who are three times more likely to get heart failure than controls. Cumulative dose of the anthracycline chemotherapy, doxorubicin, is strongly associated with increased risk of heart failure, such that patients are limited to a lifetime cumulative dose, even if the therapy is still needed. Doxorubicin is commonly used for treatment of lymphoma and high risk breast cancers, (triple negative and HER2+ breast cancer). For HER2+ patients, doxorubicin is used in combination with the HER2 targeted therapy, trastuzumab which also increases the risk of cardiotoxicity. Unfortunately, prediction of which cancer patients are at risk of heart failure is poor and current cardioprotective therapies are limited. Our published genetic studies have identified TRPC6 as a risk locus for doxorubicin-induced heart failure. Our studies of ipsc-derived cardiomyocytes and a mouse model of doxorubicin-induced cardiomyopathy showed that therapeutic inhibition of TRPC6 and TRPC6 knock-out are protective against doxorubicin-induced cardiotoxicity. Our preliminary studies and those of others suggest that inhibition of TRPC6 may also have anti-tumor properties. The overall scientific premise of this project is that genetic variants that increase TRPC6 expression or result in gain-of- function are associated with doxorubicin-related heart failure, and that characterization of TRPC6 inhibitors will improve the care of patients requiring chemotherapy. To further characterize the role of TRPC6 in doxorubicin- related heart failure, and to test the efficacy of TRPC6 inhibition in combination with doxorubicin treatment, we will: 1. Test for genetic association of TRPC6 and other known risk genes in multiple, large well characterized samples of lymphoma and breast cancer patients. 2. Determine in vitro which variants result in gain-of-function and which inhibitors prevent the gain-of-function. 3. Assess the efficacy and cardioprotection of TRPC6 inhibitors in a tumorigenic mouse model analogous to triple negative breast cancer.