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AACR 2022: Isoflavone Mitochondrial Inhibitor With Venetoclax Under Study in AML

By: Kayci Reyer
Posted: Monday, April 11, 2022

Research presented at the American Association for Cancer Research (AACR) Annual Meeting 2022 in New Orleans (Abstract 3785/16) suggests that treatment with ME-344, a novel isoflavone oxidative phosphorylation inhibitor, may be effective in patients with acute myeloid leukemia (AML). The study found that ME-344, administered either alone or in combination with the BCL2 inhibitor venetoclax, appears to be able to attack a metabolic target that is unique to this disease.

“Despite the introduction of the BCL2 inhibitor venetoclax, the overall survival, particularly in older patients, remains poor. Thus, approaches to improve the sensitivity of leukemic cells to [cytarabine]-based or BCL2-based therapies are urgently needed,” noted Natalia Baran, MD, PhD, of MD Anderson Cancer Center, Houston, and colleagues.

The study analyzed the efficacy of ME-344 in cell lines and relapsed or refractory patient samples (in vitro) and in cell lines and patient-derived xenografts (in vivo). The viability of cell lines with EC50 of 75 to 100 nM and patient samples with EC50 of 200 to 300 nM were substantially reduced following ME-344 therapy. When combined with venetoclax, ME-344 induced apoptosis and reduced MCL-1 levels. ME-344 was found to facilitate exposure of the purine biosynthetic pathway—a critical component of therapeutic efficacy, according to the study authors—by impeding biosynthetic pathways for nucleotides. It was also noted to lower the oxygen consumption rate relative to the dose received across cytarabine-resistant and cytarabine-sensitive cell lines as well as in the relapsed or refractory patient samples. This effect was magnified when ME-344 was administered with venetoclax. Finally, the combination of ME-344 and venetoclax was observed to reduce circulating leukemia burden and to improve survival outcomes in aggressive xenografts.

Disclosure: For full disclosures of the study authors, visit abstractsonline.com.


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