Neuregulin1 Alleviation of the "On-Target" Cardiotoxicity Caused by Inhibition of

Neuregulin1 减轻由抑制引起的“目标”心脏毒性

• 批准号: 8243355
• 负责人: Xinhua Yan
• 金额: $ 21.01万
• 依托单位: GENESYS RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243355
• 关键词: Adverse effects; Cancer Control; Cancer Patient; Cardiac; Cardiac Myocytes; Cardiotoxicity; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Combined Modality Therapy; Coupled; Disease-Free Survival; Dominant-Negative Mutation; Dose; Doxorubicin; ERBB2 gene; Event; Functional disorder; Future; Goals; Growth; Heart; Heart failure; Incidence; Injection of therapeutic agent; Ligands; Malignant Neoplasms; Methods; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Morphology; Mus; Mutate; Nodal; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Quality of life; Recombinants; Regimen; Risk; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Trastuzumab; Tumor Burden; Tumor Promotion; angiogenesis; cancer therapy; chemotherapy; clinical practice; improved; inhibitor/antagonist; innovation; kinase inhibitor; malignant breast neoplasm; neoplastic; novel; novel therapeutics; overexpression; prevent; receptor; trial comparing; tumor; tumor growth

DESCRIPTION (provided by applicant): A dose-related cardiotoxicity is a major clinical barrier for using the first-line chemotherapy drug doxorubicin (DOX) in cancer patients. Recently, a more severe and aggressive form of heart failure has emerged with the implementation of combination therapies that employ kinase inhibitors coupled with DOX. Clinical trials have shown that the incidence of heart failure was significantly increased in breast cancer patients treated with DOX concurrently, or sequentially, with Trastuzumab (a monoclonal antibody that blocks the HER2 receptor) compared to those treated with DOX alone. On the other hand, disease-free survival was significantly improved in patients treated with this combination therapy compared to DOX alone. These results suggest that combination of kinase inhibitor and chemotherapy, such as DOX, is necessary for achieving durable cancer control. However, concurrent use of DOX and Trastuzumab is currently discontinued because of the high incidence of severe heart failure observed in patients treated with this regimen. Instead, more conservative strategies (and therefore, less effective cancer therapy in a majority of cases), such as sequential use of DOX and Trastuzumab, are now in practice. Other strategies, such as identifying patients who are vulnerable to the potential cardiac side-effects of this type of therapy, monitoring cardiac function during therapy, cessation of therapy when cardiac dysfunction is detected, are in practice. These management methods, however, are producing several unfavorable results: they have inevitably excluded a significant number of patients from receiving combination therapy, even sequentially; they cannot produce effective and durable cancer control; and the incidence of cardiotoxicity is still increasing. These results strongly suggest that heart failure has become a major clinical obstacle to patients receiving the most effective cancer chemotherapy available. Currently, multiple clinical trials are studying the anti-neoplastic effects of PI3K inhibitors, alone or in combination with chemotherapy. The PI3K pathway, a key signaling pathway downstream of HER2, is one of the most commonly mutated pathways in cancer. More than 30 kinase inhibitors targeting this pathway have been produced. On the other hand, the PI3K pathway is crucial for protecting the heart from stress. We have shown that concurrent inhibition of the PI3K pathway exacerbated DOX-induced heart failure in mice. A critical and unmet clinical need is therapeutic strategies that will allow cancer patients to receive concurrent use of DOX and PI3K inhibitors, without increasing the risk of heart failure. Our objective is to test a novel method using Neuregulin1 (NRG1), a ligand of the HER receptors, to prevent the severe cardiotoxicity caused by therapies that concurrently use PI3K inhibitor with DOX in breast cancer patients without promoting tumor growth. The rationale for our proposal is that we showed injections of a recombinant NRG1 alleviated severe cardiac dysfunction caused by DOX in combination with cardiac-specific inhibition of PI3K in mice with cardiomyocyte specific-overexpression of a dominant negative PI3K (dnPI3K), and NRG1 injections did not alter the growth of certain tumors in mice, including those overexpressing HER2; therefore, we believe that NRG1 injections will improve cardiac function in patients treated concurrently with DOX and PI3K inhibitors without exacerbating the pre-existing tumor burden. Our Central Hypothesis is that NRG1 injections have the capacity to prevent the severe cardiotoxicity caused by concurrent use of PI3K pathway inhibitors with DOX in breast cancer-bearing mice without promoting tumor growth. Our long-term goal is to develop a novel therapeutic strategy that can be used for improving cancer control and overall quality of life. Aim 1: To determine whether or not NRG1 injections are capable of preventing the severe heart failure that can be caused by concurrent use of PI3K inhibitors with DOX in non tumor-bearing mice. Aim 2: To determine whether or not NRG1 injections will change the anti-tumor effects of DOX, PI3K inhibitors, or the combination of the two, in breast cancer-bearing mice. Aim 3: To determine whether or not NRG1 injections will provide cardioprotective effects in breast cancer-bearing mice treated with the above drugs. The proposed study is innovative in that it will develop a novel therapeutic strategy to prevent the severe heart failure that can result from using concurrent PI3K inhibitor and DOX cancer therapy. It challenges two existing scientific paradigms: (1) The PI3K pathway is indispensable for the cardioprotective effects of NRG1; (2) NRG1, a ligand of HER2, cannot be used in cancer patients due to tumor promotion potential. This study will have a significant impact on future clinical practice because this new method will increase the therapeutic window and allow more patients to receive one of the most effective cancer chemotherapies available, as well as reducing the morbidity caused by treatment-related heart failure in cancer patients. PUBLIC HEALTH RELEVANCE: The goal of this study is to develop a novel therapeutic strategy to prevent the severe heart failure that can result from using concurrent PI3K inhibitor and doxorubicin cancer chemotherapy. This study will have a significant impact on future clinical practice because this new method will increase the therapeutic window and allow more cancer patients to receive one of the most effective cancer chemotherapies available, as well as reducing the morbidity caused by treatment-related heart failure in cancer patients.

描述（由申请人提供）：与剂量相关的心脏毒性是在癌症患者中使用一线化疗药物阿霉素（DOX）的主要临床障碍。最近，随着采用激酶抑制剂与阿霉素联合治疗的联合疗法的实施，出现了一种更严重和更具侵袭性的心力衰竭。临床试验表明，与单独使用 DOX 治疗的乳腺癌患者相比，同时或序贯使用 DOX 与曲妥珠单抗（一种阻断 HER2 受体的单克隆抗体）治疗的乳腺癌患者心力衰竭的发生率显着增加。另一方面，与单独使用 DOX 相比，接受这种联合疗法治疗的患者的无病生存率显着提高。这些结果表明，激酶抑制剂和化疗（例如 DOX）的组合对于实现持久的癌症控制是必要的。然而，目前已停止同时使用 DOX 和曲妥珠单抗，因为接受该方案治疗的患者严重心力衰竭的发生率很高。相反，现在正在实践更保守的策略（因此在大多数情况下，癌症治疗效果较差），例如顺序使用 DOX 和曲妥珠单抗。其他策略，例如识别易受此类治疗潜在心脏副作用影响的患者、在治疗期间监测心脏功能、在检测到心脏功能障碍时停止治疗，均已在实践中。然而，这些管理方法正在产生一些不利的结果：它们不可避免地排除了大量患者接受联合治疗，甚至是序贯治疗；它们无法产生有效和持久的癌症控制；并且心脏毒性的发生率仍在增加。这些结果强烈表明，心力衰竭已成为接受最有效癌症化疗的患者的主要临床障碍。目前，多项临床试验正在研究PI3K抑制剂单独或与化疗联合使用的抗肿瘤作用。 PI3K 通路是 HER2 下游的关键信号通路，是癌症中最常见的突变通路之一。已经生产了超过 30 种针对该途径的激酶抑制剂。另一方面，PI3K 通路对于保护心脏免受压力至关重要。我们已经证明，同时抑制 PI3K 通路会加剧 DOX 诱导的小鼠心力衰竭。一个关键且未满足的临床需求是允许癌症患者同时使用 DOX 和 PI3K 抑制剂而不增加心力衰竭风险的治疗策略。我们的目标是测试一种使用 HER 受体配体 Neuregulin1 (NRG1) 的新方法，以预防乳腺癌患者同时使用 PI3K 抑制剂和 DOX 的治疗引起的严重心脏毒性，而不促进肿瘤生长。我们提议的基本原理是，在显性失活 PI3K (dnPI3K) 心肌细胞特异性过度表达的小鼠中，注射重组 NRG1 可减轻 DOX 联合心脏特异性 PI3K 抑制引起的严重心脏功能障碍，并且 NRG1 注射不会改变小鼠中某些肿瘤的生长，包括那些过度表达的肿瘤 HER2；因此，我们相信，NRG1 注射将改善同时接受 DOX 和 PI3K 抑制剂治疗的患者的心脏功能，而不会加剧先前存在的肿瘤负担。我们的中心假设是，NRG1 注射能够预防乳腺癌小鼠中同时使用 PI3K 通路抑制剂和 DOX 引起的严重心脏毒性，且不会促进肿瘤生长。我们的长期目标是开发一种新的治疗策略，可用于改善癌症控制和整体生活质量。目标 1：确定 NRG1 注射是否能够预防非荷瘤小鼠中同时使用 PI3K 抑制剂和 DOX 引起的严重心力衰竭。目标 2：确定 NRG1 注射是否会改变 DOX、PI3K 抑制剂或两者组合对乳腺癌小鼠的抗肿瘤作用。目标 3：确定 NRG1 注射是否会对接受上述药物治疗的乳腺癌小鼠产生心脏保护作用。拟议的研究具有创新性，因为它将开发一种新的治疗策略来预防同时使用 PI3K 抑制剂和 DOX 癌症治疗可能导致的严重心力衰竭。它挑战了两个现有的科学范式：（1）PI3K通路对于NRG1的心脏保护作用是不可或缺的； (2)NRG1是HER2的配体，由于具有促进肿瘤的潜力，不能用于癌症患者。这项研究将对未来的临床实践产生重大影响，因为这种新方法将增加治疗窗口，让更多患者接受现有的最有效的癌症化疗之一，并减少癌症患者因治疗相关心力衰竭引起的发病率。 公共健康相关性：本研究的目标是开发一种新的治疗策略，以预防同时使用 PI3K 抑制剂和阿霉素癌症化疗可能导致的严重心力衰竭。这项研究将对未来的临床实践产生重大影响，因为这种新方法将增加治疗窗口，让更多的癌症患者接受现有的最有效的癌症化疗之一，并减少癌症患者因治疗相关的心力衰竭引起的发病率。