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Preclinical evaluation of NAMPT inhibitor KPT-9274 in Acute Myeloid Leukemia

Mitchell, Shaneice Renee
http://orcid.org/0000-0001-9297-781X
http://rave.ohiolink.edu/etdc/view?acc_num=osu1546527486477125

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults affecting almost 12,000 people each year in the US. This disease is collectively characterized by an accumulation of rapidly proliferating neoplastic cells of the myeloid lineage with differentiation defects. In spite of the vast amount of information known about AML and the identification of favorable prognosis factors, a large percentage of patients relapse and succumb to this disease. In addition, the inter- and intra-tumor heterogeneity of AML makes the identification of therapeutic targets for this disease particularly challenging. Future studies are warranted to identify multi-targeted agents that could influence AML as a composite disease. A target that shows promise in targeting the bulk AML leukemic cell population is nicotinamide phosphoribosyltransferase (NAMPT). NAMPT is a protein involved in the generation of NAD+ in tumor cells, an important mediator of enzymatic reactions involved in various functions of leukemic disease progression. Leukemic blasts show a higher NAD+ turnover rate than normal cells, suggesting that NAD+ biosynthesis could be critically required in hematologic malignancies and therefore targeting the regeneration of NAD+ offers an attractive alternative strategy in AML. Inhibitors of NAMPT that have been described by others have shown potent anti-tumor activity and selectivity of several tumor models, including AML, while preserving the viability and functionality of normal tissues. While two agents targeting NAMPT have been tested in Phase I clinical trials, dose-limiting toxicities including thrombocytopenia and gastrointestinal toxicities led to their clinical discontinuation. Novel compounds with improved tolerability are needed. We sought to determine the mechanism of anti-tumor activity on AML leukemic cell population using a novel compound, KPT-9274, targeting NAMPT. We will also highlight several mechanisms used to antagonize AML disease progression via NAMPT inhibition that are cancer cell intrinsic and extrinsic, while minimizing toxicity in normal cells. To this end, I begin my studies by characterizing KPT-9274 as a selective target of AML leukemic cells. KPT-9274 was able to induce potent cytotoxicity of AML patient cells and significantly increase overall survival in murine models of disseminated AML. In addition, the selectivity of KPT-9274 allow for the overall preservation of the viability and function of normal hematopoietic cells. Further studies demonstrate that NAMPT inhibition is able to selectively target resistant-deriving leukemic stem cell population in vitro and in vivo using AML patient derived xenograft models (PDX), a more sophisticated AML mouse model to study therapeutic efficacy. Finally, I was able to demonstrate that on-target unwanted toxic effects of KPT-9274 is mitigated by the selective activation of an alternative pathway of NAD+ production via NAPRT1 and niacin supplementation. Overall, KPT-9274 demonstrates broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML. The knowledge gained from this work will facilitate the clinical development of a promising therapeutic in AML, a disease in dire need new therapeutic options.
John Byrd (Advisor)
Rosa Lapalombella (Advisor)
Sameek Roychowdhury (Committee Chair)
Vinay Puduvalli (Committee Member)
156 p.
Biomedical Research; Oncology; Pharmacology
NAMPT; AML; acute myeloid leukemia; leukemia; hematologic malignancies; metabolism; nicotinamide phosphoribosyltransferase; nicotinamide; NAD; nicotinamide dinucleotide

Recommended Citations

Citations

  • Mitchell, S. R. (2019). Preclinical evaluation of NAMPT inhibitor KPT-9274 in Acute Myeloid Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1546527486477125

    APA Style (7th edition)

  • Mitchell, Shaneice. Preclinical evaluation of NAMPT inhibitor KPT-9274 in Acute Myeloid Leukemia. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1546527486477125.

    MLA Style (8th edition)

  • Mitchell, Shaneice. "Preclinical evaluation of NAMPT inhibitor KPT-9274 in Acute Myeloid Leukemia." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1546527486477125

    Chicago Manual of Style (17th edition)

osu1546527486477125
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© 2019, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.