Individualized medicine 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)。不幸的是，对哪些癌症患者有心力衰竭风险的预测很差，而且目前还没有。 心脏保护疗法是有限的。我们已发表的遗传学研究发现TRPC6是一种易患糖尿病的风险基因。 阿霉素引起的心力衰竭。我们对IPSC来源的心肌细胞和小鼠心肌细胞模型的研究 阿霉素诱导的心肌病表明，对TRPC6和TRPC6基因敲除的治疗抑制是 对阿霉素引起的心脏毒性的保护作用。我们的初步研究和其他人的研究表明 抑制TRPC6也可能具有抗肿瘤的特性。这个项目的总体科学前提是 TRPC6和其他已知和新的基因座上的遗传变异显著增加了患者心脏毒性的风险。 对这些变体的确定和对其作用机制的更好理解将使个性化 慢性心力衰竭的风险分层和缓解。确定DOX相关的遗传风险变异 针对高危患者的心脏毒性和新的心脏保护策略，我们将：1.使我们现有的 佛罗里达州梅奥诊所心脏毒性生物储存库扩展至亚利桑那州梅奥诊所 佛罗里达州杰克逊维尔和莫菲特癌症中心对这些新登记的患者进行外显子组测序 以及使用额外的大型和多样化的数据集对热门词条进行荟萃分析。2.界定……的机制基础 TRPC6的功能增益以及与其他阿霉素诱导的毒性途径的相互作用。3.评估 TRPC6抑制剂在类三重阴性致瘤小鼠模型中的疗效和心脏保护作用 乳腺癌。

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). 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 at TRPC6 and other known and novel loci, significantly increase patient risk of cardiotoxicity. Determination of these variants and better understanding of their mechanisms of action will allow individualized risk stratification and mitigation of chronic heart failure. To determine genetic risk variants of dox-related cardiotoxicity and new cardioprotective strategies for at-risk patients, we will: 1. Diversify our existing cardiotoxicity biorepository at Mayo Clinic Florida by extending to Mayo Clinic Arizona, The University of Florida Jacksonville and Moffitt Cancer Center, performing exome sequencing of these newly enrolled patients and meta-analyses of top hits with additional large and diverse datasets. 2. Define the mechanistic basis of TRPC6 gain-of-function and interaction with other doxorubicin-induced toxicity pathways. 3. Assess the efficacy and cardioprotection of TRPC6 inhibitors in a tumorigenic mouse model analogous to triple negative breast cancer.