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Targeting AMP Synthesis to Overcome Resistance to BH3 Mimetics in Acute Myeloid Leukemia

Award Number: R01CA292893
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Targeting AMP Synthesis to Overcome Resistance to BH3 Mimetics in Acute Myeloid Leukemia - Project Summary Treatment outcomes for older patients (aged ≥60 years) with acute myeloid leukemia (AML) remain poor. Recently, combining the BH3 mimetic/BCL2 inhibitor venetoclax (VEN) with hypomethylating agents (such as azacytidine) has emerged as first-line therapy for the older AML population. Despite promising early responses, resistance to VEN, which is characterized by decreased mitochondrial apoptotic priming, emerges over time. Defining how this occurs on a molecular level is pivotal to designing effective BH3 mimetic-related combinatory therapy. My laboratory has been active in defining mechanisms underlying anti-leukemia drug resistance. Herein, using preliminary studies based on a CRISPR/Cas9 screen of BH3 mimetic-resistant AML patient-derived- xenograft (PDX) models, we reveal remarkably enhanced sensitivity to mitochondrial apoptosis after inhibition of ADSS2, a less-studied enzyme functioning in de-novo AMP biosynthesis. Mechanistically, we found that ADSS2 deficiency-mediated sensitization to BH3 mimetics was associated with downregulated AMPK activity and reduced mitochondrial adaptation, such as mitophagy. Notably, when combined with a BH3 mimetic drug, targeting de-novo AMP synthesis using an in-house ADSS inhibitor ablated AML in drug resistant animal models. Thus, we hypothesize that in drug-resistant AML, high AMP synthesis due to ADSS2 upregulation promotes AMPK signaling and antagonizes BH3 mimetic-induced apoptosis, and that targeting ADSS enzyme in combination with BH3 mimetics would eliminate AML. In Aim 1, using patient samples, we will correlate ADSS2 levels with BH3 mimetic-responsiveness in primary AML cells. We will also determine whether ADSS2 upregulation in VEN-resistant samples is due to clonal selection of pre-existing ADSS2-high cells under BH3 mimetic-pressure by integrating single-cell (sc) genotyping with scRNA-seq. In Aim 2, we will define how ADSS- dependent AMPK activity promotes poor responsiveness of AML cells to BH3 mimetics. Specifically, using mouse models, we will determine whether AMPK downregulation is required for ADSS targeting-induced mitochondrial vulnerability. We will also assess whether AMPK mediated mitophagy when activated underlies ADSS2 activity in AML. In Aim 3, we will determine whether pharmacological targeting of ADSS enzymes combined with a BH3 mimetic eliminates AML and conduct lead optimization of our ADSS inhibitors. We are the first to identify ADSS2 as a druggable target against cancer. If successful, this work would support combining a ADSS inhibitor with VEN as therapy for AML, given that the current VEN regimen has only short response duration.


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: 2026 ( Subtotal = $713,836 )
2026	2026	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	2	2/27/2026	NON-COMPETING CONTINUATION	$713,836
														Subtotal = $713,836

Issue Date FY: 2025 ( Subtotal = $734,435 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	1	3/10/2025	NEW	$734,435
														Subtotal = $734,435

Grand Total All Awards = $1,448,271

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Targeting AMP Synthesis to Overcome Resistance to BH3 Mimetics in Acute Myeloid Leukemia

Award Number: R01CA292893

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/10/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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