Christopher Y. Park, M.D., Ph.D.
2021 Funding recipient
Targeting HIF1a to Overcome Resistance to Hypomethylating Agents in Myelodysplastic Syndrome
Discovery Research Grant 2021
While much has been learned about the molecular origins of the myelodysplastic syndromes (MDS), relatively little is known about the genes that determine responses to one of the mainstays of MDS therapy –the hypomethylating agents (HMAs) – and it remains extremely difficult to predict which patients will respond to HMA therapy. Since response rates are modest and all MDS patients will eventually become refractory to HMA therapy, it is extremely important to better understand how these agents work in order to develop more effective therapeutic strategies. Our studies have identified hypoxia-inducible factor 1 alpha (HIF1α) as a critical regulator of HMA therapy resistance. Thus, we propose to determine how HIF1α induces therapy resistance, and to identify the best HIF1α inhibitors to use in combination with HMAs to maximize clinically relevant activities including the ability to reduce blasts, increase blood cell production, and eliminate MDS stem cells. The potential impact of these studies is high not only because we will investigate a novel mechanism of resistance in MDS, but because our studies also will identify optimal therapeutic reagents for use in future clinical trials. As our preliminary data indicate that HIF1α inhibition in combination with HMA therapy eliminates blasts as well as MDS stem cells, these results raise the intriguing possibility that combination therapy with a HIF1α inhibitor plus HMA may be used to treat not only high-risk MDS (the focus of most clinical studies in MDS) but lower risk patients as well. Ultimately, we anticipate our studies will provide a strong scientific rationale to initiate new clinical trials to treat MDS patients.