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Access Type
WSU Access
Date of Award
January 2023
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Cancer Biology
First Advisor
Yubin Ge
Abstract
The 5-year overall survival rate for adults with acute myeloid leukemia (AML) is only 27% and most new patients cannot tolerate the intensive standard chemotherapy. Although the FDA approved venetoclax (VEN)-based combination therapies prolong survival to some extent, resistance and relapse is common, highlighting the need of novel strategies to enhance the anti-AML activity of VEN.In line with previous literature that has shown that the suppression of oxidative phosphorylation (OXPHOS) and/or mitochondrial function enhances the antileukemic activity of VEN, this dissertation tests two different drugs, CUDC-907 and ME-344, that target OXPHOS either indirectly or directly when combined with VEN in both AML cell lines and primary patient samples. We found that while both strategies enhance the antileukemic activity of VEN againstAML cells, including those resistant to AraC, the molecular and metabolic mechanisms that contribute to this enhancement are diverse. We previously reported that CUDC-907, a dual inhibitor of PI3K and HDAC, enhances the antileukemic activity of VEN through enhancement of intrinsic apoptosis and suppression of c-Myc. This dissertation shows that CUDC-907 also suppresses OXPHOS when combined with VEN. To determine how this combination treatment leads to the suppression of OXPHOS, we performed metabolomics analyses and revealed that the drug combination hinders the supply of essential metabolites for the TCA cycle. We also found, through RNAseq analyses, that many genes encoding key enzymes for the TCA cycle are downregulated, and some of which are known c-Myc target genes. The work described in this dissertation also explores a more direct approach to enhance VEN antileukemic activity. ME-344, a second generation isoflavone, has been reported to inhibit Complex I of the electron transport chain (ETC) in solid tumors. ME-344 treatment significantly enhanced the antileukemic activity of VEN against AML, both in vitro and in vivo. However, suppression of OXPHOS by ME-344 was only observed in a subset of AML cell lines tested. Additional mechanistic studies revealed that suppression of purine biosynthesis by ME-344 represents an additional mechanism underlying the enhancement of VEN activity against AML cells, especially those with acquired resistance to AraC. Overall, results from my dissertation studies demonstrate that suppression of OXPHOS and/or purine biosynthesis is a promising strategy to enhance the antileukemic activity of VEN against AML both in vitro and in vivo.
Recommended Citation
Hurrish, Katie Hege, "Enhancing The Antileukemic Activity Of The Bcl-2 Inhibitor, Venetoclax, Against Acute Myeloid Leukemia" (2023). Wayne State University Dissertations. 3799.
https://digitalcommons.wayne.edu/oa_dissertations/3799