Alpha-Ketoglutarate Metabolism Regulates Oncometabolic Adaptation In The Heart

Introduction: The term “cancer and the heart” traditionally refers to the cardiotoxic effects of chemotherapeutic agents. However, independent of any cytostatic treatment cancer survivors have a five-fold higher risk for developing heart failure. Therefore, new therapeutic strategies must consider tumor biology when aiming at protecting the heart. In isocitrate dehydrogenase (IDH)1 and 2 mutant tumors, the elevated production of the oncometabolite D-2-hydroxyglutarate (D2-HG) is associated with systemic effects, including dilated cardiomyopathy. About 20% of acute myeloid leukemia cases harbor mutations of the IDH, which leads to reduced patient survival and causes metabolic dysfunction through production of the oncometabolite D2-HG. Recent findings have shown that D2-HG impairs oxidative decarboxylation of α-KG, which in turn increases ATP citrate lyase activity. Hypothesis: Based on these findings we are now proposing that modulation of ACL activity reverses D2-HG mediated metabolic changes. Methods: As...