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越来越重要的HF。蒽环类药物的心脏毒性，例如阿霉素（阿霉素），被广泛认可，心脏毒性是新型癌症疗法的新兴问题，例如抗体（曲妥珠单抗或赫斯蒂蛋白）和小分子激酶抑制剂（sunitinib或sunitinib或sutent）。 2009年，约有60,000名退伍军人通常用阿霉素治疗癌症。癌症药物的心脏毒性可能需要中止所需的癌症治疗，并且甚至几年或几十年后会导致HF。尽管近年来对这个问题进行了广泛讨论，但没有出现有效的治疗方法。 该项目的重点是一种新颖的想法，即心肌细胞上的α-1A-肾上腺素能受体（ARS）构成了一种内源性自适应信号系统，可保护和修复受伤后的心肌细胞。 Alpha-1-Ars以及Beta-ARS和Alpha-2-ARS是Catecholamines去甲肾上腺素和肾上腺素的G蛋白偶联受体。 Alpha-1-ARs以三个分子亚型的形式存在，称为A，B和D。Alpha-1a-ARS是一种内源防御机制的想法是基于小鼠模型的直接证据，以及来自多种动物物种和人类的支持证据。临床试验。将此内源性系统与α-1A激动剂药物一起吸收可能具有治疗性，可预防癌症药物的心脏毒性。 因此，该项目将检验以下假设：肌细胞α-1A-ARS的药物激活可以预防癌症药物心脏毒性。这项工作将通过从小鼠模型到体内大型动物（兔）和人体前体内前进，从而迈出潜在药物开发的下一个逻辑步骤。该方法将与激动剂进行治疗，这些激动剂以非常低的剂量以高效力，功效和选择性激活α-1A-AR。 计划了三个特定目标，围绕不同的实验模型组织。 目标I：测试α-1A激动剂是否在蒽环类心脏毒性的兔模型中保护。 AIM II：测试α-1A激动剂是否预防人体心肌切片中的不同癌症药物以及培养的小鼠和大鼠肌细胞。 AIM III：测试α-1A激动剂是否会降低培养的癌细胞中的癌症药物功效。 实验设计的关键方面包括与患者观察到的蒽环类药物一致的兔模型；整个治疗过程中心脏损伤和功能的详细分析；在心肌和血液中的α-1A激动剂水平的测定；保护性信号传导机制的分析；和一个体内人体心肌切片模型。 这些目标的成功完成将为预防癌症药物的心脏毒性提供进一步的临床前验证，并在大型动物中定义一种新型的内源性α-1A保护性和自适应机制在心肌细胞中。这可能是其他形式的HF进行新处理的第一步。