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.
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.
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