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Targeting mitochondria in resistant acute myeloid leukemia

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Targeting mitochondria in resistant acute myeloid leukemia
Anderson, Rebecca
Acute myeloid leukemia (AML) is an aggressive disease characterized by abnormal proliferation of myeloid cells that fail to differentiate. There have been improvements in outcomes for younger patients, however the prognosis for elderly patients, who account for the majority of cases, remains poor. One of the main reasons this outcome remains poor is due to high resistance to chemotherapy. This shows a great need for improved treatment options.In these studies we explored the role of mitochondrial metabolism in chemotherapy response. It was found that chemotherapy increases mitochondrial oxygen consumption which was found to be dependent on pyruvate dehydrogenase. Devimistat (CPI-613) is a novel lipoate derivative that inhibits pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH). Devimistat (CPI-613) sensitized AML cells to chemotherapy, indicating that mitochondrial metabolism is a source of resistance to chemotherapy. PDH deleted cells showed significantly altered mitochondria, by measure of decreased mitochondrial membrane potential and aberrant morphology. P53 loss did not alter the response to devimistat. Phase I data of devimistat in combination with high dose cytarabine and mitoxantrone showed overall response was 50%, with 26 patients showing complete remission and 5 patients showing complete remission with incomplete count recovery. Patients with poor risk cytogenetics response rate was 46%. Overall, targeting TCA cycle activity with devimistat in addition to chemotherapy is a promising approach to AML in older patients. Datasets from phase I and II clinical trials of devimistat in combination with chemotherapy demonstrated a dose response in older but not younger patients. There was an age related decline in mitochondrial function and biogenesis based on RNA sequence results from patient samples. In vitro work showed a correlation between mitochondrial membrane potential and the beneficial effects of devimistat. Additionally, we found that the electron transport chain inhibitor metformin could sensitize cells to devimistat. Devimistat showed increased reactive oxygen species and mitochondrial turnover. Inhibition of autophagy through genetic and pharmacological means sensitized cells to devimistat, as did inhibition of mitochondrial translation. Our results suggest that devimistat benefits older patients with reduced mitochondrial quality and autophagic capacity. The means by which AML cells adapt to TCA cycle inhibition by devimistat treatment is unknown. In order to understand these mechanisms, we examined glycolytic rates. Devimistat decreased the extracellular acidification rates, glucose import and glucose retention. We found that AML cells were still sensitive to a glycolytic inhibitor even with reduced glycolytic rates. Devimistat treatment promoted an increased reliance on asparagine and glutamine and asparaginase, which hydrolyzes asparagine to aspartic acid, treatment sensitized with devimistat treated AML cells. Devimistat treatment prompted AML cells to increase gene expression and protein levels of phosphoenolpyruvate carboxylase 2 (PCK2), the rate limiting step of gluconeogenesis. PDH deletion showed minimal sensitivity to an inhibitor of fatty acid oxidation. However, we showed that PDH deleted cells increased fatty acid synthesis enzymes without an increase in lipid accumulation. These results show PDH inhibition in AML cells leads to decreased glycolysis, increased reliance on amino acid metabolism, and increased gluconeogenesis. This study provide evidence that devimistat is a promising approach in combination with chemotherapy as well as in combination with amino acid deprivation, gluconeogenesis, or autophagy inhibitors.
Acute myeloid leukemia
TCA cycle
Pardee, Timothy (committee chair)
Alli, Elizabeth (committee member)
Cook, Katherine (committee member)
Kridel, Steven (committee member)
2021-01-13T09:35:29Z (accessioned)
2023-01-12T09:30:12Z (available)
2021 (issued)
Cancer Biology (discipline)
2023-01-12 (terms)
http://hdl.handle.net/10339/97960 (uri)
en (iso)
Wake Forest University

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