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

Award Number: R21CA263337
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $167,793 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	2	12/15/2023	NON-COMPETING CONTINUATION	$167,793
														Subtotal = $167,793

Issue Date FY: 2023 ( Subtotal = $238,101 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	1	12/8/2022	NEW	$238,101
														Subtotal = $238,101

Grand Total All Awards = $405,894

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

Award Number: R21CA263337

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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