Inhibition of Metabolic Enzymes as Differentiation Therapy in Acute Myeloid Leukemia
AbstractAcute myeloid leukemia (AML) is among the deadliest of cancers: it carries a 27% 5-year survival rate and is responsible for over 10,000 deaths annually in the United States alone. Despite the clear medical need, new therapeutics effective in most AML patients have not been developed in forty years, and cytotoxic chemotherapy remains the typical treatment. Fortunately, advances in the understanding of AML biology have the potential to lead to new treatments. A hallmark of AML is the differentiation block: cancer cells are halted at an early phase of hematopoietic development in which they are programmed to proliferate rapidly. In a rare subset of AML—acute promyelocytic leukemia—a genetically targeted therapy is able to overcome the differentiation block, leading to complete remissions in over 90% of patients. In this work, I describe two projects, utilizing different strategies, aimed at the development of differentiation therapy agents effective in AML more broadly.
First, I describe how frequent mutations of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) found in AML tumors inspired me to design and run a target-based compound screen with the aim of developing a chemical probe selective for the mutant allele of IDH1. The result of this effort is BRD2879, a validated inhibitor of the IDH1-R132H mutant enzyme. The compound is active in cells and possesses a structure markedly different from other known inhibitors. Second, I describe a phenotypic, cell-based screen for AML differentiation, and the target identification and validation experiments leading to the surprising discovery that inhibition of dihydroorotate dehydrogenase (DHODH)—another metabolic enzyme—reliably induces differentiation across many models of AML. I also describe my efforts to uncover a biochemical rationale for why DHODH inhibition leads to differentiation. Together, the outcomes of the two projects suggest a profound relationship between a cell’s metabolic state and its differentiation state, with the implication that modulation of a cell’s metabolism might be exploited to cause therapeutically beneficial differentiation in diseases like AML.
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