# Targeting Autocrine Hepatocyte Growth Factor (HGF) Production as a Therapeutic Modality in Acute Myeloid Leukemia (AML)

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $238,101

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute myeloid leukemia (AML), a rapidly fatal disease characterized by uncontrolled proliferation of malignant
cells in the blood and the bone marrow, is the most common acute leukemia in adults. The 5-year survival rate
remains poor (23.4%) and drops precipitously to 5% for those over age 65. Prognosis is particularly dismal for
patients with refractory disease or those who relapsed within one year of initial treatment. The standard of care
high dose chemotherapy has limited efficacy and high morbidity in this setting. Thus, this is an area with an
urgent unmet clinical need. Prior research has demonstrated that the hepatocyte growth factor (HGF)/c-MET
axis to be important for leukemia blasts survival. Based on this finding, we conducted a phase I clinical trial
using a monoclonal antibody against HGF combined with chemotherapy. This study has produced clinical
responses of ~ 55%, compared with historical response rates of only 20-25% using similar eligibility criteria
and chemotherapy backbone. Using high-dimensional, single-cell analyses of prospectively-collected
peripheral blood mononuclear cells, attenuation of p-S6 was identified as a biomarker of response and a pro-
inflammatory, type I interferon (IFN) signature and persistently elevated HGF as adverse prognostic indicators.
Differential gene expression profiling between AML cells treated in the presence and absence of the c-MET
inhibitor crizotinib suggests that the elevated HGF expression in the clinical non-responders may be mediated
by the BCL6 corepressor protein (BCOR), a member of the Polycomb complex. Our proposed study will
leverage prospectively-collected patients samples linked to annotated outcomes from this clinical trial, a novel
spatial profiling technology, and preclinical genetic models 1) to study the functional consequence of BCOR
loss on HGF expression and AML development in vivo, 2) to test the therapeutic efficacy of combining
epigenetic modulators with ficlatuzumab to treat AML and elucidate the effect of this combination on the global
chromatin state and the tumor immune microenvironment. Results generated from this study will inform
biomarker discovery for future patient stratification of clinical response and disease monitoring. This work may
also nominate potential rationale combination therapies to improve responses to the HGF antibody for patients
with de novo resistance, thus improving quality of life and overall survival for patients with AML.

## Key facts

- **NIH application ID:** 10589002
- **Project number:** 1R21CA263337-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Bradley Wayne Blaser
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $238,101
- **Award type:** 1
- **Project period:** 2022-12-08 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10589002

## Citation

> US National Institutes of Health, RePORTER application 10589002, Targeting Autocrine Hepatocyte Growth Factor (HGF) Production as a Therapeutic Modality in Acute Myeloid Leukemia (AML) (1R21CA263337-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10589002. Licensed CC0.

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