Prevention of Heart Failure induced by Doxorubicin with Early Administration of Dexrazoxane

早期给予右雷佐生预防阿霉素诱发的心力衰竭

• 批准号: 10616610
• 负责人: Hui-Ming Chang
• 金额: $ 71.07万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616610
• 关键词: ATPase Domain; Adult; Animal Model; Anthracycline; Binding; Biological Markers; Blood; Breast Cancer Patient; Breast Cancer Treatment; Cancer Patient; Cancer Survivor; Cardiac Myocytes; Cardiotoxicity; Cell Death; Cell division; Chemotherapy-Oncologic Procedure; Childhood Leukemia; Clinical; DNA; DNA Topoisomerases; Data; Dexrazoxane; Disease-Free Survival; Dose; Double-Blind Method; Doxorubicin; ERBB2 gene; Effectiveness; Electron Transport; Enrollment; Enzymes; Evaluation; FDA approved; Female Breast Carcinoma; Generations; Genes; Genetic Transcription; Half-Life; Heart failure; Hour; Human Volunteers; Intravenous; Isoenzymes; Laboratories; Left Ventricular Ejection Fraction; Mediating; Monitor; Mus; Nonmetastatic; Oncologist; Outcome; Patients; Pharmaceutical Preparations; Placebo Control; Placebos; Prevention; Proteins; Randomized; Recovery; Regimen; Solid Neoplasm; Specific qualifier value; Testing; Time; Topoisomerase; cancer cell; cancer therapy; cardiac magnetic resonance imaging; cardioprotection; chemotherapy; cost effective; gene repression; inhibitor; malignant breast neoplasm; mitochondrial dysfunction; novel; novel strategies; peripheral blood; phase III trial; preservation; prevent; primary endpoint; prospective; response; sarcoma; secondary endpoint; tumor; ubiquitin mediated proteasome degradation

Doxorubicin, an inhibitor of DNA topoisomerase 2a (Top2a), is routinely used in the treatment of breast cancer, sarcoma, and pediatric leukemia. Of the two topoisomerase 2 isozymes, Top2a is highly expressed in cancer cells and is required for cell division. However, adult cardiomyocytes express only topoisomerase 2b (Top2b), which is involved in DNA transcription, but not DNA replication. Long-term cancer survivors who were treated with doxorubicin and other anthracyclines often suffer from dose-dependent cardiotoxicity. Laboratory data showed that Top2a mediates doxorubicin’s tumoricidal activity, whereas Top2b mediates doxorubicin’s cardiotoxic effect. At present, dexrazoxane is the only FDA approved drug for cardio-protection. The cardio-protective effect of dexrazoxane is due to its ability to bind to the ATPase domain of Top2b to inhibit Top2b’s catalytic cycle. Currently, dexrazoxane is given concurrently with doxorubicin. Because dexrazoxane also binds to Top2a, it has the potential to interfere with doxorubicin’s tumoricidal effect. However, subclinical doxorubicin-induced cardiotoxicity is known to occur much earlier, perhaps at the initiation of doxorubicin therapy. Thus, dexrazoxane has limited clinical utility as specified by FDA’s approved indication. In preliminary studies, dexrazoxane induced an ubiquitin/ proteasome- mediated degradation of Top2b, but not Top2a. By administering dexrazoxane eight hours before doxorubicin, Top2b will be degraded to avoid cardiotoxicity, whereas Top2a will remain intact to preserve tumoricidal efficacy. Because the half-life of dexrazoxane is two hours, 93.75% of dexrazoxane will be eliminated eight hours (four half-lives) after administration. Indeed, dexrazoxane pre-treatment eight hours before doxorubicin provided complete protection against doxorubicin-induced cardiotoxicity in an animal model. In this proposal, this novel strategy will be tested in breast cancer patients prescribed doxorubicin- containing regimens. Two specific aims will be studied. Aim 1: To determine whether dexrazoxane given at a lower than FDA-approved dose is effective in degrading Top2b and the time-course of Top2b degradation in human volunteers. Aim 2: To test a mechanism-based hypothesis that early administration of dexrazoxane prevents doxorubicin-induced cardiotoxicity in non-metastatic, HER2- negative female breast cancer patients. HER2-negative, stage I-III female breast cancer patients will be enrolled in this prospective randomized, placebo-controlled, double-blind study. Patients will be monitored by cardiac MRI, Top2a, Top2b, and biomarkers before and after dexrazoxane/doxorubicin therapy. Tumor regression will be followed by oncologists clinically. Overall survival, event-free survival, and overall response (using response evaluation criteria in solid tumors -RECIST) will be collected to compare outcomes of cancer therapy with or without pre-treatment of dexrazoxane. Successful implementation of these trials will provide a novel and cost-effective strategy to prevent doxorubicin-induced cardiotoxicity.

阿霉素是DNA拓扑异构酶2a（Top 2a）的抑制剂，常规用于治疗乳腺癌。 癌症肉瘤和小儿白血病在两种拓扑异构酶2同工酶中，Top 2a高表达于 是癌细胞分裂所必需的。然而，成年心肌细胞仅表达拓扑异构酶2b， （Top 2b），其参与DNA转录，但不参与DNA复制。长期癌症幸存者 用多柔比星和其它蒽环类药物治疗的患者通常遭受剂量依赖性心脏毒性。 实验室数据显示Top 2a介导阿霉素的杀肿瘤活性，而Top 2b介导阿霉素的杀肿瘤活性。 介导阿霉素的心脏毒性作用。目前，右雷佐生是FDA批准的唯一用于治疗 心脏保护右雷佐生的心脏保护作用是由于其与ATP酶结合的能力 抑制Top 2b的催化循环。目前，右雷佐生与 阿霉素因为右雷佐生也与Top 2a结合，所以它有可能干扰多柔比星的抗肿瘤活性。 杀肿瘤作用。然而，已知亚临床多柔比星诱导的心脏毒性发生得更早， 可能在阿霉素治疗的开始。因此，右雷佐生的临床效用有限，如 FDA批准的适应症。在初步研究中，右雷佐生诱导泛素/蛋白酶体- 介导的Top 2b降解，但不是Top 2a。在注射前8小时注射右雷佐生 多柔比星，Top 2b将被降解以避免心脏毒性，而Top 2a将保持完整， 保持杀肿瘤功效。因为右雷佐生的半衰期是两小时，93.75%的右雷佐生 将在给药后8小时（4个半衰期）消除。事实上，右雷佐生预处理8 在多柔比星对动物中的多柔比星诱导的心脏毒性提供完全保护之前小时， 模型在这项提案中，这种新的策略将在处方阿霉素的乳腺癌患者中进行测试- 包含治疗方案。将研究两个具体目标。目的1：确定右雷佐生是否以 低于FDA批准的剂量有效降解Top 2b，并且Top 2b降解的时间过程 在人类志愿者中。目的2：检验一个基于机制的假设，即早期给予 右雷佐生预防非转移性HER 2阴性女性中阿霉素诱导的心脏毒性 乳腺癌患者。HER 2阴性、I-III期女性乳腺癌患者将入组本研究。 前瞻性随机、安慰剂对照、双盲研究。将通过心脏MRI监测患者， 右雷佐生/阿霉素治疗前后的Top 2a、Top 2b和生物标志物。肿瘤消退将是 其次是临床肿瘤学家。总生存期、无事件生存期和总缓解（使用缓解 实体瘤的评价标准-RECIST），以比较癌症治疗的结果， 不经右雷佐生预处理。这些试验的成功实施将提供一种新的， 预防多柔比星诱导的心脏毒性的成本效益策略。