Navtemadlin (KRT-232), a Small Molecule MDM2 Inhibitor, Is More Effective Than Decitabine Against Myeloproliferative Neoplasm-Blast Phase in a Patient-Derived Xenograft Model

Patients with myeloproliferative neoplasm-blast phase (MPN-BP) have a particularly dismal prognosis with a median survival of less than 6 months with currently available therapies (Mesa Blood 2015). Decitabine is the standard of care for MPN-BP. Recently, using xenotransplantation assays, we have shown that MPN-BP originates at the hematopoietic stem cell (SC) level (Wang Blood 2018) and that MPN-BP CD34 + cells contain higher levels of MDM2 protein compared with their normal counterparts (% of MDM2 + CD34 + cells: MPN-BP: 76.4±3.3; Normal: 17.5±6.4. P <0.05). MDM2 negatively regulates p53 activity and MDM2 inhibitors can activate p53 and induce apoptosis of TP53 WT cancer cells. As mutations or deletions of TP53 occur infrequently in MPN-BP, we examined the effects of a potent MDM2 inhibitor, navtemadlin (KRT-232; Canon Mol. Cancer Ther. 2015) and decitabine as monotherapy or in combination on the depletion or elimination of MPN-BP cells in a patient derived xenograft (PDX) model.