# Targeting NAMPT in Acute Myeloid Leukemia

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $461,498

## Abstract

PROJECT SUMMARY
Acute Myeloid Leukemia (AML) is a heterogeneous disease characterized by an accumulation of rapidly
proliferating neoplastic cells of the myeloid lineage with differentiation defects. The hallmarks of leukemic cells
in AML include increased cell survival, as well as altered cellular metabolism and mitochondrial functionality. In
spite of the vast amount of information known about AML and the identification of favorable prognosis factors, a
very large proportion of patients relapse and die from their disease. The inter- and intra-tumor heterogeneity of
AML makes the identification of therapeutic targets for this disease particularly challenging. Therefore, there is
an urgent need to identify multi-targeted agents that could target AML as a composite disease. Nicotinamide
phosphoribosyltransferase (NAMPT) is a protein involved in the generation of NAD+ in tumor cells. 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. Unlike many targeted therapies that can only be directed at one genetic/molecular
subtype of AML, targeting regeneration of NAD+ via NAMPT inhibition could be relevant to a much broader group
based upon the metabolic differences between tumor and normal cells. 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. Our studies
utilize a novel NAMPT inhibitor, KPT-9274, developed by Karyopharm Therapeutics for which our data
demonstrate potent cytotoxic effects in AML cell lines and primary AML blasts in vitro and in vivo. Preliminary
toxicology data shows acceptable properties of KPT-9274, which differentiate it from other previously examined
NAMPT inhibitors. KPT-9274 is currently being examined in a phase 1 study for solid tumor patients. Our
preliminary data demonstrates that inhibition of NAMPT using KPT-9274, leads to increased apoptosis and
decreased proliferation of AML cell lines and primary AML cells with minimal toxicity in normal hematopoietic
cells. KPT-9274 was also able to prolong the time to disease progression in vivo and improve overall survival in
an AML cell line-disseminated xenograft mouse model. With this proposal we aim to 1) to determine how NAMPT
affects metabolism and self-renewal in AML immature myeloid cells and their normal counterparts while
examining for distinct subtypes of AML that might be exquisitely sensitive to this class of drugs; 2) test rational
combination therapies as well as identify novel synthetic lethal partners with NAMPT inhibitors; and 3) to initiate
a Phase Ib/II trial with KPT-9274 as single agent priming followed by combination with decitabine that includes
detailed ph...

## Key facts

- **NIH application ID:** 10459455
- **Project number:** 5R01CA223165-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Rosa Lapalombella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $461,498
- **Award type:** 5
- **Project period:** 2018-08-02 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459455

## Citation

> US National Institutes of Health, RePORTER application 10459455, Targeting NAMPT in Acute Myeloid Leukemia (5R01CA223165-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459455. Licensed CC0.

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