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Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic Cancer

Award Number: R37CA237421
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic Cancer - ABSTRACT (From Parent Grant) Pancreatic cancer is a devastating disease with a five-year survival rate below 10%. One of the main factors underscoring this low survival rate is the lack of effective clinical treatments. The chemotherapy gemcitabine is the most widely used agent for pancreatic cancer due to its well tolerated profile, even though treatment only marginally extends survival. In other cancers, gemcitabine can be very effective. The limited utility of gemcitabine in pancreatic cancer is thought to result from non-cancerous cells in the tumor creating a physical barrier limiting drug delivery. According to this model, chemotherapeutic agents are unable to penetrate the tumor and reach the cancer cells. We found that tumor associated macrophages (TAMs), a non-cancerous immune cell type, abundantly secrete the nucleoside deoxycytidine (dC), and this directly inhibits the cytotoxic activity of gemcitabine. In this research proposal, we will define how dC is made and released by TAMs and how dC is obtained and utilized by pancreatic cancer cells to promote gemcitabine resistance. We will also test the hypothesis that dC release is a TAM property that can be reversed by reprogramming the TAM phenotype. These studies will be accomplished using metabolomics techniques in combination with inhibitors of metabolism and signal transduction. In parallel, we will disrupt TAM-pancreatic cancer dC crosstalk in human patient-derived microtumor models and in syngeneic mouse models to determine the translation value. The clinical application of insights from these studies could have an immediate impact on patients. A means to predict gemcitabine response based on TAM properties and/or to enhance gemcitabine efficacy by targeting the TAM phenotype would increase the utility of this well-tolerated, mainstay treatment option for patients with pancreatic cancer.


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 = $357,512 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	7	4/29/2026	NON-COMPETING CONTINUATION	$357,512
														Subtotal = $357,512

Issue Date FY: 2025 ( Subtotal = $360,340 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	001	6	5/13/2025	EXTENSION WITH OR WITHOUT FUNDS	$336,696
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	002	6	6/18/2025	EXTENSION WITH OR WITHOUT FUNDS	$24,322
2025	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	5	4/14/2025	NON-COMPETING CONTINUATION	-$678
														Subtotal = $360,340

Issue Date FY: 2024 ( Subtotal = $352,808 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	5	3/12/2024	NON-COMPETING CONTINUATION	$334,239
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	001	5	4/23/2024	NON-COMPETING CONTINUATION	$18,569
														Subtotal = $352,808

Issue Date FY: 2023 ( Subtotal = $364,847 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	4	11/28/2022	NON-COMPETING CONTINUATION	$335,064
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	001	4	3/16/2023	NON-COMPETING CONTINUATION	$29,783
														Subtotal = $364,847

Issue Date FY: 2022 ( Subtotal = $373,469 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	002	3	8/22/2022	NON-COMPETING CONTINUATION	$7,469
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	3	12/21/2021	NON-COMPETING CONTINUATION	$336,123
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	001	3	5/10/2022	NON-COMPETING CONTINUATION	$29,877
														Subtotal = $373,469

Issue Date FY: 2021 ( Subtotal = $374,610 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	001	2	1/28/2021	NON-COMPETING CONTINUATION	$18,731
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	2	11/19/2020	NON-COMPETING CONTINUATION	$355,879
														Subtotal = $374,610

Issue Date FY: 2020 ( Subtotal = $369,245 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	001	1	2/4/2020	NEW	$8,899
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	1	11/25/2019	NEW	$360,346
														Subtotal = $369,245

Grand Total All Awards = $2,552,831

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Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic Cancer

Award Number: R37CA237421

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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