Devimistat is a novel TCA cycle inhibitor being studied in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML. A combined analysis of the phase I and II datasets was conducted to determine the optimal phase III dose. A dose response in older but not younger patients was observed. Gene set enrichment analysis of RNA sequence data from patient samples revealed an age-related decline in mitochondrial function and biogenesis. In cell line models there was a strong direct correlation between the baseline mitochondrial membrane potential and the sensitizing effects of devimistat and metformin could render resistant cells sensitive. Additional mechanistic studies revealed that TCA cycle inhibition with devimistat or by genetic manipulation induced mitochondrial turnover. Pharmacological or genetic inhibition of mitophagy sensitized AML cells to devimistat. These data support a model whereby devimistat preferentially benefits older patients with reduced mitochondrial quality and biosynthetic capacity.
Anderson, Rebecca and Miller, Lance D. and Isom, Scott and Chou, Jeff W. and Pladna, Kristin M. and Schramm, Nathaniel J. and Ellis, Leslie R. and Howard, Dianna S. and Bhave, Rupali and Manuel, Megan and Dralle, Sarah and Lyerly, Susan and Powell, Bayard L. and Pardee, Timothy S., Devimistat Induces Mitophagy and Chemosensitization Resulting in Increases in Survival in Older But Not Younger AML Patients. Available at SSRN: https://ssrn.com/abstract=3569536 or http://dx.doi.org/10.2139/ssrn.3569536
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