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

描述（由申请人提供）：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，随着采用激酶抑制剂与DOX联用的联合治疗的实施，出现了更严重和更具侵袭性的心力衰竭形式。临床试验表明，与仅用DOX治疗的患者相比，在用DOX同时或顺序地用曲妥珠单抗（一种阻断HER 2受体的单克隆抗体）治疗的乳腺癌患者中心力衰竭的发生率显著增加。另一方面，与单用DOX相比，用这种联合疗法治疗的患者的无病生存率显著提高。这些结果表明，激酶抑制剂和化疗（如DOX）的组合对于实现持久的癌症控制是必要的。然而，由于在接受该方案治疗的患者中观察到重度心力衰竭的发生率较高，目前已停止DOX和曲妥珠单抗的同时使用。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。其他策略，如识别易受此类治疗的潜在心脏副作用影响的患者，在治疗期间监测心脏功能，当检测到心脏功能障碍时停止治疗，正在实践中。然而，这些管理方法产生了一些不利的结果：它们不可避免地将大量患者排除在接受联合治疗之外，即使是顺序治疗;它们不能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，心力衰竭已成为患者接受最有效的癌症化疗的主要临床障碍。目前，多项临床试验正在研究PI 3 K抑制剂单独或与化疗联合的抗肿瘤作用。PI 3 K通路是HER 2下游的关键信号通路，是癌症中最常见的突变通路之一。已经产生了30多种针对该途径的激酶抑制剂。另一方面，PI 3 K通路对于保护心脏免受压力至关重要。我们已经表明，同时抑制PI 3 K通路加剧了小鼠中DOX诱导的心力衰竭。一个关键且未满足的临床需求是允许癌症患者接受DOX和PI 3 K抑制剂同时使用而不增加心力衰竭风险的治疗策略。我们的目的是测试一种使用HER受体配体Neuregulin 1（NRG 1）的新方法，以防止在乳腺癌患者中同时使用PI 3 K抑制剂和DOX而不促进肿瘤生长的治疗引起的严重心脏毒性。我们的建议的基本原理是，我们表明注射重组NRG 1减轻了DOX联合心脏特异性抑制PI 3 K在心肌细胞特异性过表达显性负性PI 3 K（dnPI 3 K）的小鼠中引起的严重心功能障碍，并且NRG 1注射没有改变小鼠中某些肿瘤的生长，包括过表达HER 2的肿瘤;因此，我们相信NRG 1注射将改善同时用DOX和PI 3 K抑制剂治疗的患者的心脏功能，而不加重预先存在的肿瘤负荷。我们的中心假设是，NRG 1注射剂有能力预防在乳腺癌荷瘤小鼠中同时使用PI 3 K通路抑制剂和DOX引起的严重心脏毒性，而不会促进肿瘤生长。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NRG 1注射液是否能够预防非荷瘤小鼠中PI 3 K抑制剂与DOX同时使用可能引起的严重心力衰竭。目标二：确定NRG 1注射是否会改变DOX、PI 3 K抑制剂或两者联合在乳腺癌荷瘤小鼠中的抗肿瘤作用。目的3：确定NRG 1注射液是否会在用上述药物治疗的乳腺癌荷瘤小鼠中提供心脏保护作用。这项拟议的研究是创新的，因为它将开发一种新的治疗策略，以预防可能由同时使用PI 3 K抑制剂和DOX癌症治疗引起的严重心力衰竭。它挑战了两个现有的科学范式：（1）PI 3 K通路对于NRG 1的心脏保护作用是不可或缺的;（2）NRG 1，HER 2的配体，由于肿瘤促进潜力，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，让更多的患者接受现有最有效的癌症化疗之一，并降低癌症患者治疗相关心力衰竭引起的发病率。

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.