Session: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster III
Hematology Disease Topics & Pathways:
AML, Diseases, Non-Biological, Biological Processes, Myeloid Malignancies, pharmacology
We show that inhibition of NAMPT using the agent KPT-9274 induces loss of glycolytic and mitochondrial activity, more specifically a depleted total spare reserve capacity (p<0.001), in MV4-11 and THP-1 cell lines. KPT-9274 treatment decreased colony formation in AML patient samples across multiple genotypes (p<0.001) with a minimal decrease in colony formation by normal CD34+ hematopoietic cells. In addition, KPT-9274 treatment of AML cells decreased re-plating capacity, suggesting decreased self-renewal capacity (p=0.031). In contrast to pre-clinical activity observed in AML, there was minimal depletion of absolute counts observed in cell numbers of B, T and NK-lymphocyte treated ex-vivo as measured by flow cytometry, suggesting potent selectivity of KPT-9274. Furthermore, in a PDX mouse model of AML, KPT-9274 treatment significantly reduced disease burden (p<0.001) and prevented leukemic infiltration in spleen, bone marrow, and liver. In addition, KPT-9274 treatment induced differentiation, which is evident by a decrease in blast percentage and an introduction of segmented and band neutrophils in bone marrow differentials. Mice treated with KPT-9274 showed a reduction of bone marrow CD34+/CD38- cells (p<0.001), which are considered the stem cell population within the bulk leukemic cells. Extending our findings, consecutive re-plating of KPT-9274-treated PDX leukemic cells showed a marked decrease in colony formation, indicative of a loss of self-renewal capacity. KPT-9274 in combination with the anthracycline doxorubicin further decreased the infiltration of AML cells in comparison to either treatment alone. Overall, our data show that the NAMPT inhibitor KPT-9274 targets the leukemia initiating cell population, a potential source of resistance to cytotoxic chemotherapy, which is not adequately eradicated by current therapies in most patients.
Disclosures: Mims: Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Baloglu: Karyopharm Therpeutics: Employment. Senapedis: Karyopharm Therapeutics: Employment. Byrd: Jazz: Honoraria; Acerta: Honoraria, Research Funding; Pharmacyclics: Research Funding.
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