Doxorubicin (DOX) is a powerful chemotherapeutic agent that is largely used in the clinical practice for cancer treatment. Unfortunately, nearly 30% of DOX-treated patients develop heart failure, which represents the first noncancer-related cause of death in these patients. The molecular mechanisms underlying DOX-induced cardiotoxicity remain largely unclear. Our preliminary results indicate that the kinase MST1 is involved in DOX-induced cardiomyopathy. MST1 is a major component of the Hippo pathway, which negatively regulates cell survival and growth and was previously shown to contribute to myocardial injury in response to stress. We will study the phenotype of mice with cardiomyocyte-specific MST1 gene deletion treated with DOX. We will elucidate the molecular mechanisms through which MST1 contributes to DOX-induced cardiomyopathy, with a focus on the involvement of SIRT3.
SIGNIFICANCE AND INNOVATION
In Aim1, we will clarify the role of MST1 activation in response to chronic low-dose DOX-treatment. We will study for the first time the effects of cardiac MST1 inhibition in a murine model of chronic DOX-induced cardiomyopathy. Moreover, we will study the effects of a recently discovered MST1-inhibiting drug in vivo, i.e. XMU-MP-1, and provide a cutting-edge tool for a possible clinical post-chemotherapy cardiological management of DOX-treated patients. To further enforce the clinical relevance of our study, we will also assess for the first time the effects of DOX on MST1 in human samples.
In Aim 2, we will study for the first time the interaction between the stress-response protein MST1 and SIRT3, a key player for mitochondrial function and cell survival. We will generate cardiac-specific knockout models to dissect the molecular pathway that links MST1 to SIRT3. The dissection of this pathway represents a potential keystone that may highlight new therapeutic targets for the treatment of DOX-induced cardiotoxicity.
TRANSLATIONAL RELEVANCE AND IMPACT FOR THE NATIONAL HEALTH SYSTEM
Despite many improvements in the understanding of the pathophysiology of DOX-induced cardiomyopathy, this disease still represents the first non-cancer cause of death for breast-cancer survivors, killing nearly 30% of DOX-treated patients within 5 years. Recent translational clinical trials failed to provide the expected protective effects and the only effective way to mild the cardiotoxic effect of DOX is to lower its dosage. Patients developing heart failure after DOX treatment may experience several episodes of hospitalization before death, with a high cost for the National Health System (SSN). The proposed project may constitute an original, cutting-edge tool to counteract the iatrogenic cardiotoxic effects of DOX, and responds to Horizon 2020 priorities for the development of personalized treatments for chronic medical conditions. Our study may provide a solid basis for the development of novel efficient pharmacological translational strategies for the treatment of DOX-induced induced cardiomyopathy. These therapies could strongly reduce the high social and medical costs for the clinical management of this disease with a considerable positive impact on the National Health Service.
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