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

TRPC6 的表征可预测和预防化疗相关心力衰竭

• 批准号: 10705329
• 负责人: Nadine Norton
• 金额: $ 49.76万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705329
• 关键词: 5' Flanking Region; ABCB1 gene; Address; Adult; African American; Alleles; Anthracycline; Antineoplastic Agents; Apoptosis; Arrhythmia; Black American; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Lymphoma; Calcium; Cancer Patient; Cancer cell line; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Characteristics; Clinic; Clinical Trials; Code; Data; Data Set; Databases; Dose; Doxorubicin; ERBB2 gene; Endothelial Cells; Enrollment; Estrogens; Exposure to; Family member; Female; Gene Expression; Genes; Genetic Markers; Genetic study; Genotype; Heart; Heart failure; Human; In Vitro; Incidence; Introns; Kidney Diseases; Knock-out; Knowledge; Left Ventricular Ejection Fraction; Left ventricular structure; Literature; Lymphoma; Malignant Childhood Neoplasm; Maps; Mus; National Surgical Adjuvant Breast and Bowel Project; Outcome; Pathway interactions; Patient Care; Patient risk; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Phenotype; Pre-Clinical Model; Prevention strategy; Property; Publishing; Quantitative Trait Loci; RARG gene; Research; Resistance; Risk; Risk Factors; Risk Marker; Role; Sampling; Site; Testing; Therapeutic; Time; Toxic effect; Trastuzumab; Untranslated RNA; Variant; base; biobank; cancer therapy; cardioprotection; chemotherapy; cohort; early phase clinical trial; efficacy testing; exome; gain of function; genetic association; genetic variant; genome wide association study; heart function; high risk; improved; induced pluripotent stem cell derived cardiomyocytes; inhibitor; male; malignant breast neoplasm; migration; mortality; mouse model; neoplastic; novel; older women; prevent; promoter; prospective; risk variant; targeted treatment; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumorigenic

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.

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）。对于 HER2+ 患者，阿霉素与 HER2 靶向治疗曲妥珠单抗联合使用 这也会增加心脏毒性的风险。不幸的是，预测哪些癌症患者有患癌症的风险 心力衰竭的情况很差，目前的心脏保护疗法也很有限。我们发表的遗传学研究 确定 TRPC6 是阿霉素诱发心力衰竭的风险位点。我们对 ipsc 衍生的研究 心肌细胞和阿霉素诱导的心肌病小鼠模型表明，治疗性抑制 TRPC6 和 TRPC6 敲除可预防阿霉素诱导的心脏毒性。我们的初步 研究和其他研究表明，抑制 TRPC6 也可能具有抗肿瘤特性。整体 该项目的科学前提是增加 TRPC6 表达或导致增益的遗传变异 功能与多柔比星相关的心力衰竭有关，TRPC6 抑制剂的表征将 改善需要化疗的患者的护理。为了进一步表征 TRPC6 在阿霉素中的作用 相关的心力衰竭，并测试 TRPC6 抑制与阿霉素治疗联合的疗效，我们 将： 1. 在多个、大型、已明确表征的样本中测试 TRPC6 和其他已知风险基因的遗传关联 淋巴瘤和乳腺癌患者的样本。 2. 体外确定哪些变异会导致功能获得 以及哪些抑制剂会阻止功能获得。 3. 评估TRPC6的功效和心脏保护作用 类似于三阴性乳腺癌的致瘤小鼠模型中的抑制剂。

项目成果

TRPC6 N338S is a gain-of-function mutant identified in patient with doxorubicin-induced cardiotoxicity.

TRPC6 N338S 是在阿霉素诱导的心脏毒性患者中发现的功能获得突变体。

• DOI: 10.1016/j.bbadis.2022.166505
• 发表时间: 2022-07-01
• 期刊: Biochimica et biophysica acta. Molecular basis of disease
• 作者: T. Lu;Xiaojing Sun;B. Necela;Hon;N. Norton
• 通讯作者: N. Norton