Abstract 5709: Disruption of mitochondrial metabolism underlies the efficacy of devimistat in acute myeloid leukemia
Authors: Reid Michael A. , Bose Shree , Xiao Zhengtao , Mikhael Peter G. , Liu Juan , Locasale Jason W. , Pardee Timothy S. 
Published: September 2020

Abstract
Background: Acute myeloid leukemia (AML) remains an agressive malignancy with poor clinical outcomes, particularly in older patients. Dysregulated metabolism has long presented a promising target for cancer therapeutics; however, the development of clinical-stage therapies targeting cancer cell metabolism has been limited and faces challenges to achieve both efficacy and acceptable toxicity. As an exception, the lipoic acid analogue devimistat has shown positive clinical outcomes in numerous early-phase clinical trials including for relapsed and refractory AML patients. While inhibition of lipoic acid-dependent ketoacid dehydrogenase (KADH) enzymes has been proposed as the mechanism of these antineoplastic effects, the mechanisms underlying the efficacy devimistat and its possible relation to metabolism in patients has not been established.
Methods: Samples of bone marrow and blood plasma from patients with relapsed or refractory AML before and after treatment with devimistat were collected. The samples were analyzed using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) methods to profile ~400 polar metabolites. Kinetic flux profiling in cultured cancer cell lines treated with devimistat was also performed.
Results: Analysis of blood plasma samples collected following devimistat treatment revealed detectable levels of drug, consistent with clinically therapeutic concentrations. Comprehensive metabolite profiling of pretreatment and posttreatment blood plasma samples revealed distinct metabolic alterations induced by devimistat administration. Devimistat is thought to inhibit ketoacid dehydrogenase (KADH) enzyme, and consistent with this proposed mechanism of action, accumulations of KADH substrates were observed in the posttreatment samples. Local metabolism in the tumor microenvironment was also altered by devimistat therapy, with robust reductions of TCA intermediates measured in bone marrow plasma samples collected after treatment. Interestingly, quantification of these metabolites revealed an association between overall clinical outcomes and changes in concentrations of bone marrow metabolites. Kinetic flux tracing demonstrated an expected reduction of mitochondrial metabolic flux in cultured tumor cells following treatment with devimistat.
Conclusions: Comprehensive metabolite profiling reveals that devimistat targets KADH enzymes and reduces mitochondrial metabolism in humans. Furthermore, these metabolic changes are quantitatively associated with clinical outcomes, posing a potential opportunity for biomarker development and precision metabolic therapy.
Citation Format: Michael A. Reid, Shree Bose, Zhengtao Xiao, Peter G. Mikhael, Juan Liu, Jason W. Locasale, Timothy S. Pardee. Disruption of mitochondrial metabolism underlies the efficacy of devimistat in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5709.