Characterization and Targeting of Metabolic Vulnerabilities of Myelodysplastic Stem Cells
EvansMDS Young Investigator Award
The objective of this project is to develop novel strategies for the treatment of myelodysplastic syndrome (MDS) based on the characterization and targeting of MDS stem cells. To date, few therapeutic strategies have been developed to specifically target MDS stem cells. We have shown through a careful and thorough characterization of MDS stem cells the following properties: 1) up-regulation of cell surface protein CD123 2) altered energy metabolism 3) differential increase of protein synthesis machinery over normal HSCs. Based on these characteristics we have developed two therapeutic strategies for high risk MDS stem cells that employ targeting of protein synthesis with omacetaxine or targeting oxidative phosphorylation with venetoclax. We have demonstrated using advanced preclinical methods (primary MDS specimens, xenograft models) that both regimens efficiently target MDS stem cells. Furthermore, these agents are able to selectively eradicate MDS stem cells while having little effect on normal stem cells. These exciting findings are being investigated in patients in two currently ongoing clinical trials at the University of Colorado (see letter from D. Pollyea) that test omacetaxine or venetoclax-based regimens. In the phase 1 portion of our omacetaxine + azacitidine study for previously untreated high grade MDS patients, all 3 patients who have completed at least 1 month of treatment to date have experienced a complete remission, in some cases with eradication of cytogenetic abnormalities, which would be unexpected if evaluating azacitidine alone after one cycle of therapy in these patients. These studies will characterize the efficacy of MDS stem cell targeting for patients, the mechanisms driving sensitivity or resistance to metabolically-based therapy, and the contributions of metabolism to MDS pathogenesis and progression. Through detailed examination of patients in these studies we will test the hypothesis that MDS stem cells in high risk patients can be eradicated in vivo with the protein synthesis inhibitor omacetaxine and/or venetoclax. Furthermore, we hypothesize that changes in metabolism contribute to MDS progression during early stages of disease pathogenesis and represent a potential therapeutic target.