Stephen Oh, MD

Project Title: Leveraging NFKB Pathway Dysregulation for Therapeutic Benefit in Myeloproliferative Neoplasms

We have utilized single cell mass cytometry to interrogate aberrant signaling networks in Myeloproliferative neoplasms (MPNs). These studies led to the identification of hyperactivated NFκB Pathway signaling in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML). We have Recently obtained preliminary data indicating that the NEDD8 activating enzyme inhibitor pevonedistat (which has known activity against NFκB signaling) can differentially inhibit colony growth from MF Patient vs normal CD34+ cells. In a pilot experiment with the MPL W515L retroviral mouse model, Reductions in WBC and GFP% as well as prolonged survival were observed in individual mice treated with pevonedistat. Based on these findings, we hypothesize that therapeutic efficacy in MPNs can be achieved by targeting NFκB with pevonedistat. To test this hypothesis, we propose to determine how pevonedistat modulates MPN stem/progenitor cell signaling/growth, and to optimize therapeutic applications of pevonedistat in murine MPN models. These studies address the focus of the MPN Challenge Grant on the elimination of mutant stem cells and have the potential to lead directly to novelTherapies for MPN patients.

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