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Targeting Metabolic Crosstalk in Pancreatic Cancer

Award Number: R37CA283575
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Targeting Metabolic Crosstalk in Pancreatic Cancer - Project Summary / Abstract Pancreatic ductal adenocarcinoma (PDA) is a devastating disease lacking effective treatment options. PDA is characterized by a dense and fibrotic tumor microenvironment deposited by extensive and diverse fibroblast and immune cell populations within this niche. The diversity of cell types within PDA tumors also extends to cancer cells themselves, as heterogenous subpopulations of cancer cells are capable of symbiotic behaviors that support resistance to therapy. Accordingly, targeting crosstalk interactions can remove barriers to allow more effective clinical treatment. Investigating clonal PDA behaviors, we have identified two metabolic subpopulations differentiated by their sensitivity to mitochondrial inhibition. Metabolic exchange between these populations confers resistance mediated by asparagine that is overproduced and released through a constitutively active integrated stress response in the insensitive clones. Further, we observed that degradation of asparagine functions to sensitize PDA to mitochondrial inhibitors. Targeting mitochondrial metabolism in PDA cells functions to lower intercellular nucleotide pools that compete with standard of care chemotherapy, pyrimidine anti-metabolites. Further, targeting mitochondrial metabolism also functions to reduce the anti- inflammatory polarization of tumor-associated macrophages that provide non-cell autonomous chemoresistance. This research proposal will target factors underpinning the programming of PDA cells that produce and release asparagine (Aim 1). We have identified oncogenic and stress pathways that can be targeted to impair the survival of asparagine producing cells and disrupt metabolic crosstalk. Further, we have identified that asparagine producing PDA cells have hypermethylated histones that correlate with a mesenchymal state. Accordingly, we will leverage metabolic approaches to normalize the histone methylation and reprogram these cells to desensitize them to mitochondrial inhibition. In parallel, we will combine treatment of mitochondrial inhibitors potentiated through asparagine degradation and with standard of care chemotherapy (Aim 2). Both systemic and local asparagine levels will be targeted and compared for efficacy in enhancing mitochondrial inhibitors. These experiments will be performed in multiple human and murine tumor models, and analyzed through a combination of techniques that will allow for in vivo assessment of PDA metabolic subtype response to therapy. Finally, we will characterize the remodeling of the immune and stromal compartments of PDA tumors in response to mitochondrial inhibitors potentiated by asparagine degradation to identify new immune targeting approaches. Together, these data will provide important insights into mechanisms that maintain cancer cell heterogeneity and generate important pre-clinical data examining the impact of targeting metabolic crosstalk pathways to enhance PDA response to therapy.


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: 2025 ( Subtotal = $445,319 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	2	4/10/2025	NON-COMPETING CONTINUATION	$400,786
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	2	5/22/2025	NON-COMPETING CONTINUATION	$44,533
														Subtotal = $445,319

Issue Date FY: 2024 ( Subtotal = $436,431 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	1	4/24/2024	NEW	$436,431
														Subtotal = $436,431

Grand Total All Awards = $881,750

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Targeting Metabolic Crosstalk in Pancreatic Cancer

Award Number: R37CA283575

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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