# A Targeted Combination Therapy Approach for AML

> **NIH NIH R03** · EMORY UNIVERSITY · 2020 · $156,000

## Abstract

PROJECT SUMMARY/ ABSTRACT
Treatment of acute myeloid leukemia (AML) has improved but five-year survival rates are still <60% for adult
and pediatric patients. Current therapies are very toxic, can cause long-term side effects, and are often
contraindicated for elderly patients. Our goal is to develop a molecularly-targeted therapy for AML with better
efficacy and reduced toxicity. MERTK tyrosine kinase is ectopically expressed in >90% of pediatric and adult
AML patient samples. MRX-2843 is a novel small molecule that inhibits MERTK and FLT3, a known
therapeutic target in AML. MRX-2843 has robust activity in preclinical models and is currently in phase I clinical
trials; however, the utility of molecularly-targeted monotherapies has been limited by development of
resistance. Thus, we sought to identify signaling pathways that synergize with MRX-2843 to inhibit leukemia
cell expansion. Using a kinase inhibitor library screen, we found synergistic interactions between MRX-2843
and RKI-1447, an inhibitor of rho-associated protein kinases (ROCK1 and ROCK2). ROCK1 down-regulation
reduces leukocyte affinity for chemokines in the protective bone marrow niche and ROCK inhibition reduces
expansion of AML blasts in patient sample cultures, induces AML cell death, and prolongs survival in murine
AML models. MRX-2843/RKI-1447 combination therapy synergistically reduced AML cell expansion in vitro
and these effects correlated with changes in cell cycle progression and induction of apoptosis. Preliminary data
also suggest that ROCK1/2 inhibition can promote AML sensitivity to MRX-2843 in the bone marrow. We
hypothesize that simultaneous inhibition of ROCK1/2 and MERTK/FLT3 will decrease disease burden and
prolong survival, both alone and in combination with standard AML induction chemotherapy, in murine AML
models. To test this idea, the impact of treatment with MRX-2843, GSK269962A, and/or chemotherapy will be
determined in mice with human AML cell line and/or patient derived xenografts. To identify the targets
important for therapeutic synergy, shRNA-expressing cell line derivatives (shMERTK, shROCK1, shROCK2,
shCONTROL) will be tested in xenograft models in combination with MRX-2843, GSK269962A, or vehicle. To
further evaluate the ability of the combination therapy to target bone marrow disease, the impact of treatment
with MRX-2843 and/or GSK269962A will be determined using 3-dimensional biomimicry cultures derived from
a panel of AML patient samples, which recapitulate many features of the normal bone marrow niche, including
protection from chemotherapy, and provide a robust platform for therapeutic testing. Together these
experiments will assess the utility of ROCK1/2 and MERTK/FLT3 inhibitor combination therapies for treatment
of AML, provide important information about the efficacy and toxicity of the combination therapy in preclinical
mouse models, and may lead to development of a powerful approach to treat AML more effectively and with
less toxicity b...

## Key facts

- **NIH application ID:** 10047167
- **Project number:** 1R03CA246039-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Dawn Elizabeth Barnes
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,000
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047167

## Citation

> US National Institutes of Health, RePORTER application 10047167, A Targeted Combination Therapy Approach for AML (1R03CA246039-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10047167. Licensed CC0.

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