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

描述(申请人提供)：剂量相关的心脏毒性是癌症患者使用一线化疗药物阿霉素(DOX)的主要临床障碍。最近，随着联合治疗的实施，出现了一种更严重和更具侵袭性的心力衰竭形式，这种联合治疗使用了激酶抑制剂和DOX。临床试验表明，与单独使用DOX治疗的患者相比，同时或顺序使用曲妥珠单抗(一种阻断HER2受体的单抗)治疗的乳腺癌患者心力衰竭的发生率显著增加。另一方面，与DOX单独治疗相比，接受这种联合治疗的患者的无病存活率显著提高。这些结果表明，为了实现持久的癌症控制，联合使用激酶抑制剂和化疗(如DOX)是必要的。然而，同时使用DOX和曲妥珠单抗目前已停止使用，因为在接受该方案治疗的患者中观察到严重心力衰竭的高发生率。相反，更保守的策略(因此，在大多数情况下癌症治疗效果较差)，如顺序使用DOX和曲妥珠单抗，现在正在实践中。其他战略，例如确定哪些患者容易受到这种治疗的潜在心脏副作用的影响，在治疗过程中监测心脏功能，在检测到心脏功能障碍时停止治疗，都在实践中。然而，这些管理方法产生了几个不利的结果：它们不可避免地排除了大量患者接受联合治疗，即使是顺序治疗；它们无法产生有效和持久的癌症控制；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现有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下游的一个关键信号通路，是癌症中最常见的突变通路之一。目前已有30多种针对该途径的激酶抑制剂被生产出来。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。一个关键且未得到满足的临床需求是治疗策略，该策略将允许癌症患者同时使用DOX和PI3K抑制剂，而不会增加心力衰竭的风险。我们的目标是测试一种新的方法，使用HER受体的配体NeuRegin1(NRG1)来预防乳腺癌患者在不促进肿瘤生长的情况下同时使用PI3K抑制剂和DOX所引起的严重心脏毒性。我们提出建议的理由是，我们发现注射重组NRG1可以缓解DOX引起的严重心功能障碍，同时结合心脏特异性抑制PI3K基因(DnPI3K)，并且注射NRG1没有改变某些肿瘤在小鼠体内的生长，包括那些过表达HER2的肿瘤；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功能，而不会加剧原有的肿瘤负担。我们的中心假设是，NRG1注射有能力在不促进肿瘤生长的情况下，防止PI3K途径抑制剂与DOX在乳腺癌荷瘤小鼠中同时使用而引起的严重心脏毒性。我们的长期目标是开发一种新的治疗策略，用于改善癌症控制和整体生活质量。目的1：确定NRG1注射是否能够预防非荷瘤小鼠同时使用PI3K抑制剂和DOX所引起的严重心力衰竭。目的：确定注射NRG1是否会改变DOX、PI3K抑制剂或两者合用对乳腺癌小鼠的抗肿瘤作用。目的：确定NRG1注射剂对上述药物治疗的乳腺癌小鼠是否具有心脏保护作用。这项拟议的研究具有创新性，因为它将开发一种新的治疗策略，以预防同时使用PI3K抑制剂和DOX癌症疗法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，由于肿瘤促进作用，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，使更多患者能够接受现有最有效的癌症化疗之一，并降低癌症患者因治疗相关心力衰竭而导致的发病率。 公共卫生相关性：这项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，使更多的癌症患者能够接受现有最有效的癌症化疗之一，并降低癌症患者因治疗相关的心力衰竭而导致的发病率。

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.