# XPO1 inhibitors Selinexor and Eltanexor in Combination with Venetoclax and Decitabine (ASTX727) in AML

> **NIH NIH UM1** · DANA-FARBER CANCER INST · 2021 · $124,999

## Abstract

a) Project Summary
Our studies have shown that the nuclear export inhibitors selinexor and eltanexor are highly active
against AML cells and leukemia initiating cells (LICs) in patient-derived xenograft (PDX) models
of human AML, with minimal toxicity to normal hematopoietic and progenitor cells (HSPCs)
(Leukemia, 2013 and Leukemia, 2015). Thus, selinexor or eltanexor treament provides a
therapeutic window for elimination of relapse-driving LICs while sparing normal cells. Our
published earlier studies show that the BCL2 protein prevents XPO1 inhibitor mediated cell death,
which suggests that selinexor or eltanexor will be highly synergistic and produce greater AML cell
death if given in combination with a BCL2 inhibitor. Combinations of the BCL2 inhibitor
venetoclax plus the methylation inhibitor decitabine (dacogen) have been shown to induce
remission in AML (DiNardo CD et al. Blood 2019). Both venetoclax and selinexor or eltanxor are
active against LICs as well as fast-proliferating bulk AML cells in patient-derived xenograft (PDX)
models suggesting the hypothesis that selinexor or eltanexor together with venetoclax, and the
decitabine equivalent ASTX727 will exhibit synergy in killing the LIC that sustain the AML cells
in patients. Based on this hypothesis, we will perform preclinical studies to test the activity of
selinexor or eltanexor in combination with venetoclax and dacogen against bulk AML cells and
LICs in AML PDX models with NPM1 mutations. In Aim 1 we will determine the maximum
tolerated dose of selinexor or eltanexor in combination with venetoclax and ASTX727 in NSG
mice. In Aim2 we will compare the activity of venetoclax plus ASTX727 with the activity of all
three drugs together to assess the added benefit of selinexor or eltanexor in killing AML LIC and
determine disease-free survival. In Aim 3 we will assess the mechanism of drug interactions by
measuring apoptosis by TUNEL assay on LICs and performing BH3 profiling of patient AML
cells prior to therapy.
It is becoming very clear that achieving complete cure for AML will require combination of
multiple non-cross-resistant therapeutics. Thus, our goal for the UM1 award is to perform the
preclinical studies to test the activity of selinexor, eltanexor, venetoclax and decitabine against
AML cells and LICs to promote the prompt advancement of this multi-drug therapy into the clinic.

## Key facts

- **NIH application ID:** 10337728
- **Project number:** 3UM1CA186709-06S2
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** KEITH T FLAHERTY
- **Activity code:** UM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $124,999
- **Award type:** 3
- **Project period:** 2021-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337728

## Citation

> US National Institutes of Health, RePORTER application 10337728, XPO1 inhibitors Selinexor and Eltanexor in Combination with Venetoclax and Decitabine (ASTX727) in AML (3UM1CA186709-06S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10337728. Licensed CC0.

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