Targeting early erythroid progenitor deficiency to treat myelodysplastic syndrome
EvansMDS Young Investigator Award
Myelodysplastic syndrome (MDS) is a lethal hematopoietic malignancy with very limited therapeutic options. The proposed project will provide novel therapies for treatment-refractory MDS by targeting the insufficiency of early erythroid progenitors that contributes to refractoriness of MDS patients to current therapies. We have utilized both chemical and CRISPR/Cas9 genomic screens and hematopoietic lineage conditional knockout models to identify and confirm a protein target as a novel regulator of early erythroid progenitor self-renewal and demonstrated that pharmacological inhibition of this regulator corrects anemia of MDS with sustainable long-term efficacy in a genetically engineered Mx1-Cre Srsf2 P95H/WT MDS model in vivo. We have further demonstrated that this inhibitor triggered expansion of erythroid progenitors isolated from MDS patients.
I am currently engaged in a collaboration to translate this promising therapeutic strategy into phase 1 clinical trials for erythropoietin-refractory MDS. Having demonstrated that this inhibitor corrected anemia of MDS in the Srsf2P95H genetic background, I plan to further assess the efficacy of this inhibitor in multiple murine genetic models of MDS carrying different genetic abnormalities and to identify genetic markers of response to this inhibitor using primary MDS patient samples. As part of the collaboration, I plan to modify the structure of this inhibitor through medicinal chemistry to increase specificity and optimize drug metabolism and pharmacokinetic properties. Together, these efforts will help to move our discoveries forward into clinical trials for MDS.