Predictive targeting of mitochondrial metabolism in Acute Myeloid Leukemia patients with a lipoic acid analog

Targeting metabolism has long been a theory for cancer therapy, but clinical development has been limited by toxicities, compound availability, overall efficacy, and patient specificity1. CPI-613, a lipoic acid analogue that interferes with enzymes involved in mitochondrial metabolism, has demonstrated clinical activity in lethal malignancies including relapsed or therapy refractory Acute Myeloid Leukemias (AMLs)2,3 and Phase III trials are ongoing1. Using metabolomics, we investigated blood and bone marrow samples from a cohort of 29 relapsed or refractory AML patients involved in Phase I and II studies undergoing CPI-613 treatment (NCT01768897, NCT02484391) including 13 that achieved a complete response. We show that CPI-613 treatment in patients induced defined alterations related to the tricarboxylic acid (TCA) cycle and associated redox, anabolic and catabolic metabolism. These findings are consistent with targeting of several ketoacid dehydrogenase (KADH) enzymes that use lipoic acid as a cofactor and are related to mitochondrial metabolism. The alterations were observed systemically but were more pronounced within the leukemic bone marrow microenvironment consistent with its mechanistic target. Machine learning revealed that metabolic status and changes associated with mitochondrial metabolism were predictive of treatment response, indicating that mechanism-based metabolite biomarkers to a targeted metabolic cancer therapy may be feasible. Finally, we confirm using isotope tracing and flux analysis that these effects are due to disruptions to substrate utilization into the mitochondria. Our findings provide evidence that a tolerated, anti-cancer therapeutic can act by targeting mitochondrial metabolism in humans.