Project Term
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Project Summary
Myelodysplastic syndrome (MDS) is a fatal disease with limited therapeutic opportunities. To increase survival rate, it is essential to identify therapeutic targets specific for MDS stem and progenitor cells (MDS-SC), the source of the disease. MDS-SC uniquely upregulate nicotinamide metabolism. We thus aim to understand its importance on MDS-SC function and survival using multi-omics analysis. Completion of the study will have identified a new treatment modality to improve MDS patient outcome.
Lay Abstract
The goal of this proposal is to improve treatment outcomes for patients diagnosed with myelodysplastic syndrome (MDS). MDS is a type of blood disorder caused by accumulation of abnormal blood cells and reduced generation of normal blood cells. Despite decades of extensive effort to develop effective treatments, the clinical picture for patients with MDS has been poor - only approximately 30% of patients respond to current therapies. Additionally, despite receiving proper care and treatment, a significant percentage of MDS patients progress to blood cancer which has an even worse prognosis than MDS. As seen with cancer, the reason for poor response in MDS patients are the rare abnormal blood cells that are the source of the disorder, termed as MDS stem cells. To improve MDS patient outcome, it is thus essential to eliminate these MDS stem cells. To effectively eliminate the MDS stem cells without impacting the normal cells, we need to understand the unique properties of MDS stem cells. Our lab has previously shown that MDS stem cells are more metabolically active. Our preliminary data suggests that a naturally occurring chemical called NAD is required to maintain the unique metabolic state of MDS stem cells, whereas normal stem cells can survive using alternative mechanisms. NAD metabolism is thus a unique property of MDS stem cells which we hypothesize represents a therapeutic vulnerability – the focus of this proposal. Our preliminary data has shown that inhibiting NAD metabolism preferentially kills MDS stem cells while sparing normal cells. We will use MDS patient samples to further validate how NAD metabolism is important for MDS stem cell metabolism, function and survival. Successful completion of this work will have characterized the unique metabolic properties of MDS stem cells, an unanswered avenue, which will greatly improve our understanding of MDS stem cells. Additionally, we will have characterized a unique strategy to eliminate MDS stem cells. The positive outcome of this pre-clinical work has the potential to lead into a Phase I/II clinical trial with the goal of improving clinical responses. Altogether, our work stands to significantly improve outcomes for patients with MDS.
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