Identifying metabolic drivers of cancer cachexia-associated cardiomyopathy

About This Grant

PROJECT SUMMARY. Cancer cachexia (CC) is a syndrome of progressive body weight loss, muscle wasting, and functional decline that occurs in 30% of all cancer patients, and 70-90% of patients with gastrointestinal, lung, and liver malignancies. CC causes severe weakness and fatigue and increases morbidity and mortality. Twenty percent of cancer patients die of CC, and yet, there are limited therapeutic options. Cardiac atrophy and deficits in contraction and relaxation of the heart occur in CC patients, which contribute to worsened clinical outcomes. Very little is known mechanistically about the cardiac pathology in CC. The long-term objective is to identify molecular mechanisms underlying atrophy and mechanical dysfunction in CC-associated heart muscle disease (cardiomyopathy), with the goal of discovering therapeutic targets to optimize clinical care for CC patients. This project will identify metabolic drivers of CC cardiomyopathy through chemical and genetic targeting of mitochondrial function, which will be accomplished through two specific aims: (1) Pre-clinical cancer cachexia mouse models will be used to identify the role of mitochondrial dysfunction on metabolism and mechanical function in hearts and cardiac muscle cells (myocytes) from mice with CC. Mice with and without tumors will be treated with a mitochondrial stabilizer (SS-31) or vehicle. SS-31 binds to cardiolipin in the inner mitochondrial membrane and stabilizes cristae structure and integrity of energy production machinery. At the study endpoint, mitochondrial function, substrate utilization and energy production, oxidative stress, and cardiac function will be assessed using state of the art methodologies including 3D holotomograpy, cryo-electron microscopy, mitochondrial metabolic flux analysis, isolated cardiac myocyte contractility and calcium cycling measurements, and in vivo cardiac function using echocardiography, electrocardiography, and exercise stress testing. The hypothesis is that improving mitochondrial health will restore cardiac function. (2) An in vitro model of simulated CC-associated cardiomyopathy consisting of primary cell cultures of neonatal rat ventricular myocytes (NRVM) co-cultured with C26 tumor cells will be used to assess small interfering RNA knockdown (KD) of the enzyme prolyl hydroxylase 2 (PHD2). PHD2 KD will be performed in NRVM prior to C26 co-culture to induce acute hypoxia response signaling with the goal of protecting myocytes against mitochondrial destabilization and dysfunction associated with CC. We will use similar methodologies in aim 2 to measure mitochondrial function, cellular substrate utilization and energy production, oxidative stress, and calcium cycling. Together, these aims interrogate molecular mechanisms related to mitochondrial membrane stability and hypoxia signaling in CC- associated cardiomyopathy and identify cause-effect relationships between these mechanisms and contractility and calcium cycling function in CC hearts. These studies will provide new insights about the causes of CC- associated cardiomyopathy, which will enable development of improved treatment options for patients with CC, optimizing quality and length of life for individuals with this devastating cancer-related syndrome.