Doctor of Philosophy, The Ohio State University, 2022, Pharmaceutical Sciences

Acute myeloid leukemia (AML) is one of the most lethal forms of hematologic malignancies with low survival rates (<8%) in patients older than 60. With FDA-approved targeted therapies and immunotherapies and advancement of sequencing techniques, the treatment strategies for AML has undergone a paradigm shift in the last decade. But because of inter- and intra-patient heterogeneity, identification of a therapy that can broadly target different subtypes of AML is very challenging. Two mutations and/or concurrent signaling abnormalities are needed to synergistically license leukemia initiation and maintenance. NAMPT is a rate-limiting NAD+ generation enzyme, involving in various functions of leukemia cells. Upon discovery of the roles of NAMPT in metabolic reprograming, small inhibitors that target NAMPT have been soon developed. In our published studies, we showed that NAMPT inhibitor, KPT-9274, was able to induce potent cytotoxicity of AML patient cells and provided survival benefit for murine models of disseminated AML. NAMPT inhibition can selectively eliminate leukemia stem cell population. Although NAMPT inhibitors demonstrated exciting preclinical properties, dose-limiting toxicities including thrombocytopenia and gastrointestinal toxicities were observed. KPT-9274 exhibited gender-dependent toxicity in kidney and anemia, highlighting the necessity of identification of synthetic lethal partners for KPT-9274 treatment. By using CRISPR screen, we were able to identify histone acetylases, HDAC8 and SIRT6, as co-essential genes with KPT-9274 treatment. HDAC8 or SIRT6 inhibition sensitized AML cell lines and primary patient cells to NAMPT inhibition. Importantly, a pan-HDAC inhibitor, AR-42, eliminated leukemia initiating cells (LICs) in vitro and in vivo in combination with KPT-9274 by altering transcriptional patterns of LICs and shutting down multiple DNA repair pathways. Understanding of cooperativity of co-mutations in driving leukemogenesis offers another me (open full item for complete abstract)

Committee: Rosa Lapalombella (Advisor); John Byrd (Committee Member); Sharyn Baker (Committee Member); Moray Campbell (Committee Member) Subjects: Bioinformatics; Cellular Biology; Molecular Biology; Pharmaceuticals; Pharmacology; Pharmacy Sciences

Doctor of Philosophy, The Ohio State University, 2019, 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 v (open full item for complete abstract)

Committee: John Byrd (Advisor); Rosa Lapalombella (Advisor); Sameek Roychowdhury (Committee Chair); Vinay Puduvalli (Committee Member) Subjects: Biomedical Research; Oncology; Pharmacology