Novel therapy for cardiotoxicity of cancer drugs

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。癌症药物的毒性是一种越来越重要的HF类型。蒽环类药物，例如阿霉素（阿霉素）的心脏毒性是公认的，心脏毒性是新的癌症治疗，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）的一个新出现的问题。2009年，约60，000名退伍军人患有通常用阿霉素治疗的癌症。癌症药物的高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导致HF。虽然这个问题近年来被广泛讨论，但没有有效的治疗方法。 该项目的重点是新的想法，即心肌细胞上的α-1A-肾上腺素能受体（AR）包括一个内源性适应性信号系统，在损伤后保护和修复心肌细胞。α-1-AR，沿着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。α-1-AR存在三种分子亚型，命名为A、B和D。α-1A-AR是一种内源性防御机制的想法是基于来自小鼠模型的直接证据，以及来自多个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是预防癌症药物心脏毒性的治疗方法。 因此，本项目将检验药物激活肌细胞α-1A-ARs可以预防癌症药物心脏毒性的假设。这项工作将采取潜在药物开发的下一个合乎逻辑的步骤，从小鼠模型推进到大型动物（兔）体内和人类体外。该方法将使用激动剂进行治疗，这些激动剂以非常低的剂量以高效力，有效性和选择性激活α-1A-AR。 三个具体的目标是计划，围绕不同的实验模型组织。 目的I：测试α-1A激动剂是否在蒽环类药物心脏毒性的兔模型中具有保护作用。 目的II：测试α-1A激动剂是否在人类心肌切片中保护免受不同癌症药物的侵害， 培养的小鼠和大鼠肌细胞。 目的III：测试α-1A激动剂是否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中观察到的蒽环类药物给药一致的兔模型;整个治疗过程中心脏损伤和功能的详细分析;心肌和血液中α-1A激动剂药物水平的测定;保护性信号传导机制的分析;以及离体人心肌切片模型。 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型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的新型内源性α-1A保护和适应机制。这可能是其他形式HF新治疗的第一步。

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.