Heart Failure in Cancer Patients

项目描述（由申请人提供）：本项目主要关注许多癌症患者面临的两个关键问题：1)使用损伤心脏的抗癌药物引起的心脏毒性和2)癌症引起的心脏恶病质引起的心功能障碍。这两个问题都没有得到医生的充分重视，这导致了发病率，在某些情况下，死亡。在本项目中，我们建议解决这些缺陷。在目标1中，我们建议使用斑马鱼作为从蛋白激酶抑制剂类中识别抗癌药物的工具。鉴于啮齿动物模型在识别有问题的激酶抑制剂方面还不是很有效，我们的初步研究表明斑马鱼可能是一个可行的哨兵。我们已经并将在目前市场上的12种药物以及未来将进入市场的其他药物上测试这一假设。此外，我们将使用这些药物作为工具来确定各种蛋白激酶在心脏中所起的作用-这是一个我们知之甚少的领域。这应该允许我们在问题药物被广泛使用之前预测它们。第二个问题是癌症引起的心脏恶病质，它对心脏的影响，以及调节它的信号通路。据估计，恶病质及其后遗症是约30%癌症患者死亡的原因。最重要的是，根据我们在啮齿动物模型中的发现，我们概述了限制或预防癌症引起的心脏恶病质的策略。值得注意的是，这些策略依赖于多年来在心力衰竭患者中使用的药物。由于这些药物已经被fda批准用于心力衰竭患者，如果我们在其他啮齿动物模型中的发现与我们已完成的研究一致，我们建议将这些药物进行临床试验。总之，我们相信我们的研究可以带来新的诊断和治疗方法，以改善癌症患者的生活。

DESCRIPTION (provided by applicant): This Project is focused on two critical issues that many cancer patients have to face: 1) the cardiotoxicity resulting from the use of anti-cancer drugs that injure the heart and 2) the cardiac dysfunction that arises from cancer induced cardiac cachexia. Neither of these issues are sufficiently appreciated by physicians, and this leads to morbidity and, in some cases, mortality. In this Project we propose to address these deficiencies. In Aim 1 we propose to employ the zebrafish as a tool to identify anti-cancer drugs from the class of protein kinase inhibitors. Whereas rodent models have not been very effective in identifying problematic kinase inhibitors, our preliminary studies suggest the zebrafish may be a viable sentinel. We have, and will, test this hypothesis on each of the 12 drugs that are currently on the market, and on additional agents that will reach the market in the future. Furthermore, we will use these drugs as tools to identify the roles played by various protein kinases in the heart- an area about which we know very little. This should allow us to predict problematic agents before they are in widespread use. The second issue will address is cancer-induced cardiac cachexia, its consequences on the heart, and the signaling pathways that regulate it. Cachexia and its sequellae are estimated to be the cause of death in approximately 30% of cancer patients. Most importantly, we have outlined strategies, based on our findings in rodent models that limit or prevent cancer-induced cardiac cachexia. Remarkably, these strategies rely on agents that have been used in heart failure patients for years. Since these drugs are already FDA-approved for use in heart failure patients, we are proposing to go to clinical trial with these agents if our findings in additional rodent models concur with our completed studies. In summary, we believe that our studies could lead to novel diagnostic and therapeutic approaches to better the lives of cancer victims.