Individualized medicine to predict and prevent chemotherapy-related heart failure

预测和预防化疗相关心力衰竭的个体化药物

基本信息

批准号：
10714111
负责人：
Nadine Norton
金额：
$ 66.01万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714111
关键词：
Accounting Adult African African American Anthracycline Antineoplastic Agents Apoptosis Arizona Arrhythmia Breast Cancer Patient Breast Cancer Risk Factor Breast Cancer Treatment Breast Lymphoma Calcium Cancer Center Cancer Patient Cancer cell line Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Clinic Clinical Trials Congestive Heart Failure Data Set Dose Doxorubicin ERBB2 gene Endothelial Cells European Exposure to Family member Florida Gene Expression Gene Frequency Genes Genetic Markers Genetic Risk Genetic Variation Genetic study Heart failure Human Incidence Knock-out Left Ventricular Ejection Fraction Lymphoma Malignant Childhood Neoplasm Maps Meta-Analysis Metabolism Mus National Surgical Adjuvant Breast and Bowel Project Pathway interactions Patient risk Patients Pharmaceutical Preparations Phenotype Population Population Heterogeneity Prevention strategy Property Publishing Risk Risk Factors Sampling TP53 gene Testing Therapeutic Toxic effect Translations Universities Variant Woman Work biobank cardioprotection chemotherapy diverse data early phase clinical trial efficacy evaluation exome exome sequencing gain of function genetic variant genome wide association study heart function high risk improved individualized medicine induced pluripotent stem cell derived cardiomyocytes inhibitor inter-individual variation male malignant breast neoplasm mortality mouse model mutant novel participant enrollment patient population prevent rare variant response risk mitigation risk prediction risk stratification risk variant treatment strategy triple-negative invasive breast carcinoma tumor tumorigenic

项目摘要

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.

项目概要/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淋巴瘤患者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增加密切相关，例如即使仍然需要治疗，患者的终生累积剂量也受到限制。阿霉素是常用于治疗淋巴瘤和高风险乳腺癌（三阴性和 HER2+ 乳腺癌）癌症）。不幸的是，目前对哪些癌症患者有心力衰竭风险的预测很差心脏保护疗法是有限的。我们发表的遗传学研究已确定 TRPC6 是以下疾病的风险位点：阿霉素诱发的心力衰竭。我们对 ipsc 衍生的心肌细胞和小鼠模型的研究阿霉素诱导的心肌病表明，TRPC6 和 TRPC6 敲除的治疗性抑制防止阿霉素引起的心脏毒性。我们和其他人的初步研究表明抑制 TRPC6 也可能具有抗肿瘤特性。该项目的总体科学前提是 TRPC6 和其他已知和新位点的遗传变异显着增加患者心脏毒性的风险。确定这些变异并更好地了解其作用机制将允许个体化治疗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心脏毒性和针对高危患者的新心脏保护策略，我们将： 1. 使我们现有的多元化佛罗里达州梅奥诊所的心脏毒性生物储存库扩展到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入组的患者进行外显子组测序以及对其他大型和多样化数据集的热门点击进行荟萃分析。 2. 定义机制基础 TRPC6 功能获得以及与其他阿霉素诱导的毒性途径的相互作用。 3. 评估 TRPC6抑制剂在类似于三阴性的致瘤小鼠模型中的功效和心脏保护作用乳腺癌。