Heart Failure in Cancer Patients

癌症患者的心力衰竭

• 批准号: 9284514
• 负责人: Hind Lal
• 金额: $ 39.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284514
• 关键词: Address; Adverse effects; Affect; Animal Model; Antineoplastic Agents; Area; Awareness; BAY 54-9085; Cachexia; Cancer Model; Cancer Patient; Cardiac; Cardiotoxicity; Cardiovascular system; Cause of Death; Cessation of life; Clinic; Clinical; Clinical Trials; Comorbidity; Data; Development; Diagnosis; Drug Targeting; Drug usage; FDA approved; Face; Fishes; Functional disorder; Future; Hand; Health Care Costs; Heart; Heart failure; Impairment; Incidence; Knowledge; Lead; Malignant Neoplasms; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial dysfunction; Oligonucleotides; Oncologist; Pathology; Patients; Pharmaceutical Preparations; Phosphotransferases; Physicians; Play; Process; Protein Kinase; Protein Kinase Inhibitors; Publishing; Quality of life; Reproducibility; Rodent Model; Role; Scourge; Sentinel; Signal Pathway; Stress; Testing; Therapeutic; Toxic effect; Transgenic Organisms; Work; Zebrafish; base; cancer cachexia; cancer therapy; cardiac cachexia; injured; kinase inhibitor; knock-down; mortality; mouse model; novel diagnostics; novel strategies; novel therapeutic intervention; pre-clinical; prevent; prophylactic; protein kinase inhibitor; public health relevance; screening; small molecule; targeted treatment; tool; virtual; wasting

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.

描述（由申请人提供）：该项目重点关注许多癌症患者必须面对的两个关键问题：1）使用损伤心脏的抗癌药物导致的心脏毒性和2）癌症引起的心脏功能障碍诱发心脏恶病质。医生都没有充分认识到这些问题，这会导致发病率，在某些情况下甚至导致死亡。在这个项目中，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。虽然啮齿动物模型在识别有问题的激酶抑制剂方面并不是很有效，但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 种药物以及未来将上市的其他药物中测试这一假设。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——我们对此知之甚少。这应该使我们能够在有问题的药物被广泛使用之前对其进行预测。第二个问题将讨论癌症引起的心脏恶病质、其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% 癌症患者的死亡原因。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。由于这些药物已获得 FDA 批准用于心力衰竭患者，因此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，我们建议使用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。

项目成果

Report on the international colloquium on cardio-oncology (rome, 12-14 march 2014).

国际心脏肿瘤学学术研讨会报告（罗马，2014 年 3 月 12-14 日）。

• 发表时间: 2014
• 作者: Ewer, Michael;Gianni, Luca;Pane, Fabrizio;Sandri, Maria Teresa;Steiner, Rudolf K;Wojnowski, Leszek;Yeh, Edward T;Carver, Joseph R;Lipshultz, Steven E;Minotti, Giorgio;Armstrong, Gregory T;Cardinale, Daniela;Colan, Steven D;Darby, Sarah C;For
• 通讯作者: For

Physiological, pharmacological and toxicological considerations of drug-induced structural cardiac injury.

药物引起的结构性心脏损伤的生理学、药理学和毒理学考虑。

• 发表时间: 2015-02
• 影响因子: 7.3
• 作者: Cross, M J;Berridge, B R;Clements, P J M;Cove;Force, T L;Hoffmann, P;Holbrook, M;Lyon, A R;Mellor, H R;Norris, A A;Pirmohamed, M;Tugwood, J D;Sidaway, J E;Park, B K
• 通讯作者: Park, B K

Cancer treatment-related cardiotoxicity: current state of knowledge and future research priorities.

癌症治疗相关的心脏毒性：当前的知识状况和未来的研究重点。

• 发表时间: 2014-09
• 作者: Shelburne, Nonniekaye;Adhikari, Bishow;Brell, Joanna;Davis, Myrtle;Desvigne;Freedman, Andrew;Minasian, Lori;Force, Thomas;Remick, Scot C
• 通讯作者: Remick, Scot C

Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue.

酪氨酸激酶抑制剂介导的大鼠工程心脏组织收缩力下降的分析。

• 发表时间: 2016
• 影响因子: 3.7
• 作者: Jacob, Fabian;Yonis, Amina Y;Cuello, Friederike;Luther, Pradeep;Schulze, Thomas;Eder, Alexandra;Streichert, Thomas;Mannhardt, Ingra;Hirt, Marc N;Schaaf, Sebastian;Stenzig, Justus;Force, Thomas;Eschenhagen, Thomas;Hansen, Arne
• 通讯作者: Hansen, Arne