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一线化疗药物多柔比星（DOX）在癌症患者中使用的主要临床障碍。最近，随着激酶抑制剂与DOX联合治疗的实施，出现了一种更严重和侵袭性的心力衰竭。临床试验表明，与单独接受DOX治疗的乳腺癌患者相比，同时或依次接受曲妥珠单抗（一种阻断HER2受体的单克隆抗体）治疗的DOX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，采用这种联合治疗的患者的无病生存期显著提高。这些结果表明，联合使用激酶抑制剂和化疗（如DOX）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，因为在使用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，效果较差的癌症治疗），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潜在心脏副作用影响的患者，在治疗期间监测心功能，在检测到心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：它们不可避免地使大量患者无法接受联合治疗，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PI3K抑制剂单独或联合化疗的抗肿瘤作用。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。针对这一途径的激酶抑制剂已经有30多种。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，PI3K途径的同时抑制加剧了dox诱导的小鼠心力衰竭。一个关键且未被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使用神经调节蛋白1 (NRG1) （HER受体的配体）的新方法，以防止在不促进肿瘤生长的情况下，在乳腺癌患者中同时使用PI3K抑制剂和DOX的治疗引起的严重心脏毒性。我们的建议的基本原理是，我们发现在心肌细胞特异性过表达显性负PI3K （dnPI3K）的小鼠中，注射重组NRG1减轻了DOX引起的严重心功能障碍，并结合心脏特异性抑制PI3K，并且NRG1注射不会改变小鼠某些肿瘤的生长，包括过表达HER2的小鼠；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，而不会加重已有的肿瘤负担。我们的中心假设是NRG1注射能够预防PI3K途径抑制剂与DOX同时使用对乳腺癌小鼠造成的严重心脏毒性，而不促进肿瘤生长。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。目的1：确定NRG1注射是否能够预防非荷瘤小鼠因PI3K抑制剂与DOX同时使用而引起的严重心力衰竭。目的2：在乳腺癌小鼠中，确定NRG1注射是否会改变DOX、PI3K抑制剂或两者联合的抗肿瘤作用。目的3：确定NRG1注射是否对经上述药物治疗的乳腺癌小鼠具有心脏保护作用。该研究的创新之处在于，它将开发一种新的治疗策略，以预防PI3K抑制剂和DOX癌症治疗同时使用可能导致的严重心力衰竭。它挑战了两种现有的科学范式：(1)PI3K通路对于NRG1的心脏保护作用是不可或缺的；(2) NRG1作为HER2的配体，由于具有促肿瘤潜能，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，并允许更多的患者接受最有效的癌症化疗之一，以及减少癌症患者因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. 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.