Abstract 18017: Metabolic Modulation as a Novel Therapy for Chemotherapy-Induced Cardiotoxicity

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Abstract

Introduction: Chemotherapy Induced Cardiotoxicity (CIC) is a serious complication that results in early termination of cancer therapies, despite responsive tumours. There are no therapies that prevent CIC, as our understanding of the mechanisms in this condition is limited. Intriguingly, similar metabolic processes (increased glycolysis) has been described in heart failure and cancer, suggesting metabolic therapies may be beneficial against both diseases. One challenge in designing CIC therapies is protecting the heart against apoptosis without hindering chemotherapy-mediated tumour apoptosis. An intriguing difference between the myocardial and tumour microenvironments is the former is normoxic (oxidized) and the latter hypoxic (reduced), suggesting that targeting metabolic redox-sensitive proteins induced by chemotherapy agents in the heart may provide selectivity against CIC, without compromising tumour suppression.

Hypothesis: We hypothesized that therapeutically targeting the metabolic redox-sensitive protein pyruvate kinase-M2 (PKM2) in the heart and tumour may have significant benefit against CIC.

Methods:In vitro: immunoblots, qRT PCR, Immunofluoresence. in-vivo: mouse xenotransplant tumour model, echocardiography, ex-vivo working heart model.

Results:In vitro, stabilization of a tetrameric form of PKM2 (with the small molecule compound TEPP-46) inhibited chemotherapy-mediated apoptosis in an oxidized environment, but enhanced apoptosis in a reduced environment. In vivo, we show that the myocardium is significantly more oxidized than the tumour and stabilization of PKM2 prevented Adriamycin-induced cardiac dysfunction, normalized abnormal cardiac metabolism, and prevented apoptosis in the heart, but further enhanced tumour apoptosis and tumour regression in xenotransplanted mice with human lung tumours.

Conclusion: Our novel data provide the first evidence that redox-targeted metabolic therapies are beneficial against CIC, while synergistically decreasing tumour growth.

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