Novel therapy for cardiotoxicity of cancer drugs

抗癌药物心脏毒性的新疗法

• 批准号: 8598801
• 负责人: PAUL C SIMPSON
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598801
• 关键词: Adrenergic Agonists; Adrenergic Receptor; Adriamycin PFS; Affinity; Agonist; Animals; Anthracyclines; Antibodies; Antineoplastic Agents; Biological Assay; Blood; Blood Pressure; Cancer cell line; Cardiac; Cardiac Myocytes; Cardiotoxicity; Catecholamines; Cessation of life; Clinical; Clinical Trials; Defense Mechanisms; Dose; Doxorubicin; Electrocardiogram; Epinephrine; Experimental Designs; Experimental Models; Fibrosis; G-Protein-Coupled Receptors; Goals; Growth; Heart; Heart failure; Hormone Receptor; Human; Injury; Lead; Learning; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Muscle Cells; Myocardial; Myocardium; Names; Norepinephrine; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Rattus; Receptor Activation; Receptors, Adrenergic, alpha-2; Research; Roche brand of trastuzumab; Safety; Signal Transduction; Slice; Sutent; System; Telemetry; Testing; Therapeutic; Toxic effect; Translating; Trastuzumab; Validation; Veterans; Work; alpha-1 adrenergic receptors; base; beta-adrenergic receptor; cancer cell; cancer therapy; drug development; drug efficacy; effective therapy; improved; in vitro testing; in vivo; kinase inhibitor; man; mouse model; novel; pre-clinical; prevent; prophylactic; public health relevance; receptor; repaired; small molecule; sobriety; statistics

DESCRIPTION (provided by applicant): Heart failure (HF) is a major clinical problem in Veterans and civilians. Cardiotoxicity of cancer drugs is a type of HF that is growing in importance. Cardiotoxicity of anthracyclines, for example doxorubicin (Adriamycin), is well recognized, and cardiotoxicity is an emerging problem with novel cancer therapies, such as antibodies (trastuzumab or Herceptin) and small-molecule kinase inhibitors (sunitinib or Sutent). In 2009, ~60,000 Veterans had cancers typically treated with doxorubicin. Cardiotoxicity of cancer drugs can require discontinuation of needed cancer therapy, and cause HF even years or decades later. Although this problem is discussed extensively in recent years, no effective treatments have emerged. This project is focused on the novel idea that alpha-1A-adrenergic receptors (ARs) on cardiac myocytes comprise an endogenous adaptive signaling system that protects and repairs myocytes after injury. Alpha-1- ARs, along with beta-ARs and alpha-2-ARs, are G-protein-coupled receptors for the catecholamines norepinephrine and epinephrine. Alpha-1-ARs exist as three molecular subtypes, named A, B, and D. The idea that alpha-1A-ARs are an endogenous defense mechanism is based on direct evidence from mouse models, plus supporting evidence from multiple animal species and human clinical trials. Engaging this endogenous system with an alpha-1A agonist drug might be therapeutic to prevent cardiotoxicity of cancer drugs. Therefore, this project will test the hypothesis that drug activation of myocyte alpha-1A-ARs can prevent cancer drug cardiotoxicity. The work will take the next logical step in potential drug development, by advancing from mouse models to a large animal (rabbit) in vivo, and human ex vivo. The approach will be treatment with agonists that activate the alpha-1A-AR with high potency, efficacy, and selectivity, at a very low dose. Three specific aims are planned, organized around different experimental models. Aim I: Test whether an alpha-1A agonist protects in a rabbit model of anthracycline cardiotoxicity. Aim II: Test if alpha-1A agonists protect against different cancer drugs in human myocardial slices and cultured mouse and rat myocytes. Aim III: Test whether alpha-1A agonists reduce cancer drug efficacy in cultured cancer cells. Key aspects of experimental design include a rabbit model consistent with anthracycline dosing observed in patients; detailed analysis of cardiac damage and function throughout treatment; assay of alpha- 1A agonist drug levels in myocardium and blood; analysis of protective signaling mechanisms; and an ex vivo human myocardial slice model. Successful completion of these Aims will provide further preclinical validation of a potential novel therapy to prevent cardiotoxicity of cancer drugs, and define in a large animal a novel endogenous alpha-1A protective and adaptive mechanism in cardiac myocytes. This can be the initial step to new treatment in other forms of HF.

描述（由申请人提供）： 心力衰竭（HF）是退伍军人和平民的主要临床问题。癌症药物的心脏毒性是一种日益重要的心力衰竭。蒽环类药物（例如阿霉素（阿霉素））的心脏毒性已得到广泛认可，并且心脏毒性是新型癌症疗法（例如抗体（曲妥珠单抗或赫赛汀）和小分子激酶抑制剂（舒尼替尼或索坦））中出现的一个新问题。 2009 年，约 60,000 名退伍军人患有通常使用阿霉素治疗的癌症。癌症药物的心脏毒性可能需要停止所需的癌症治疗，甚至在数年或数十年后也会导致心力衰竭。尽管近年来这个问题被广泛讨论，但尚未出现有效的治疗方法。 该项目的重点是心肌细胞上的 α-1A 肾上腺素受体 (AR) 包含内源性自适应信号系统，可在损伤后保护和修复心肌细胞。 Alpha-1-AR 以及 β-AR 和 α-2-AR 是儿茶酚胺、去甲肾上腺素和肾上腺素的 G 蛋白偶联受体。 Alpha-1-AR 以三种分子亚型的形式存在，分别称为 A、B 和 D。α-1A-AR 是一种内源性防御机制的观点基于来自小鼠模型的直接证据，以及来自多种动物物种和人类临床试验的支持证据。将这种内源性系统与 α-1A 激动剂药物结合可能有助于预防癌症药物的心脏毒性。 因此，该项目将检验心肌细胞α-1A-AR的药物激活可以预防癌症药物心脏毒性的假设。这项工作将在潜在的药物开发中迈出下一个合乎逻辑的步骤，从小鼠模型推进到大型动物（兔子）的体内模型和人类的离体模型。该方法将使用激动剂进行治疗，该激动剂能够以极低剂量激活具有高效力、功效和选择性的 α-1A-AR。 围绕不同的实验模型规划了三个具体目标。 目标 I：测试 α-1A 激动剂是否对蒽环类心脏毒性兔模型具有保护作用。 目标 II：测试 alpha-1A 激动剂是否可以在人心肌切片以及培养的小鼠和大鼠肌细胞中预防不同的癌症药物。 目标 III：测试 alpha-1A 激动剂是否会降低培养癌细胞中的癌症药物疗效。 实验设计的关键方面包括与患者观察到的蒽环类药物剂量一致的兔子模型；整个治疗过程中心脏损伤和功能的详细分析；测定心肌和血液中的α-1A激动剂药物水平；保护性信号机制分析；和离体人体心肌切片模型。 这些目标的成功完成将为预防癌症药物心脏毒性的潜在新疗法提供进一步的临床前验证，并在大型动物中定义心肌细胞中新的内源性 alpha-1A 保护和适应机制。这可能是其他形式心力衰竭新治疗的第一步。