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

项目总结/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 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的风险增加密切相关， 即使仍然需要治疗，患者也仅限于终身累积剂量。多柔比星 通常用于治疗淋巴瘤和高危乳腺癌（三阴性和HER 2+乳腺癌） 癌症）。对于HER 2+患者，多柔比星与HER 2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， 心力衰竭是不好的，并且目前的心脏保护疗法是有限的。我们发表的遗传学研究 确定TRPC 6为多柔比星诱导的心力衰竭的风险位点。我们对ipsc衍生的 心肌细胞和多柔比星诱导的心肌病小鼠模型显示， TRPC 6和TRPC 6敲除的表达对阿霉素诱导的心脏毒性具有保护作用。我们的初步 研究和其他人的研究表明，抑制TRPC 6也可能具有抗肿瘤特性。整体 该项目的科学前提是，增加TRPC 6表达或导致 功能与多柔比星相关的心力衰竭有关，TRPC 6抑制剂的特征将 改善对需要化疗的病人的护理。为了进一步表征TRPC 6在多柔比星中的作用， 相关的心力衰竭，并测试TRPC 6抑制与阿霉素治疗组合的功效，我们 意志：1.检测TRPC 6和其他已知风险基因在多个大型良好表征的 淋巴瘤和乳腺癌患者的样本。2.在体外确定哪些变体导致功能获得 以及哪些抑制剂阻止功能获得。3.评估TRPC 6的疗效和心脏保护作用 在类似于三阴性乳腺癌的致瘤小鼠模型中，

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.