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Branched chain amino acids and pancreatic cancer

Award Number: R01CA248315
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Branched chain amino acids and pancreatic cancer - PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) remains one of the most intractable types of cancer, with a 5-year survival rate below 9%. Alarmingly, the incidence of pancreatic cancer is on the rise over the past 20 years, with particularly sharp increases in incidence among young adults. Poor nutrition and obesity are likely culprits, with obesity and diabetes independently conferring increased risk of PDA, but the mechanisms remain unclear. Branched chain amino acids (BCAAs) have emerged as one potentially important link between diet, systemic metabolism, and PDA. We have demonstrated in previous work and preliminary data that BCAAs are avidly consumed by the pancreas, where they contribute prominently to the TCA cycle and to acetyl-CoA pools. We have also recently shown that acetyl-CoA metabolism plays a key role in facilitating pancreatic tumor initiation, leading to the hypothesis that BCAA metabolism is required for efficient pancreatic tumorigenesis. Thus, one major goal of this grant will be to test the role of BCAA catabolism in the pancreas in facilitating acinar cell plasticity and tumor formation. We will use state-of-the-art in vivo isotope tracer approaches to elucidate the fates of BCAAs in the pancreas. We will also employ nutritional, genetic (using two novel mouse models), and pharmacological approaches to define the roles of BCAA catabolism in pancreatic function and tumorigenesis. In contrast to normal pancreatic cells, use of BCAAs as a fuel source is thought to be suppressed as pancreatic cancer develops. Nevertheless, BCAAs are an important biomarker of PDA, with circulating levels elevated years prior to PDA diagnosis, indicating a risk that likely mechanistically differs from that of tumor initiation. BCAAs are also elevated in obesity and diabetes, where they promote insulin secretion and insulin resistance, promoting a hyperinsulinemic state. Insulin itself acts as a growth factor to promote anabolic signaling and metabolism in PDA cells. Our second major goal is thus to evaluate the contribution of systemic BCAA levels and hyperinsulinemia to PDA tumor growth. We will manipulate systemic BCAA levels through nutritional, genetic, and pharmacological approaches to test the impact on tumor growth. We will then query the impact of insulin directly on PDA cells and on cancer-associated fibroblasts (CAFs), along with the impact of reducing hyperinsulinemia on tumor growth. Finally, we will test the potential to target BCAA metabolism through mouse clinical trials. These studies will provide deep insight into the roles of BCAAs in multi-step PDA tumorigenesis and could lead to novel therapeutic strategies for this deadly disease.


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 = $0 )
2026	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	5	11/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $441,899 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	5	6/11/2024	NON-COMPETING CONTINUATION	$441,899
														Subtotal = $441,899

Issue Date FY: 2023 ( Subtotal = $455,856 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	4	6/16/2023	NON-COMPETING CONTINUATION	$455,856
														Subtotal = $455,856

Issue Date FY: 2022 ( Subtotal = $455,856 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	3	8/22/2022	NON-COMPETING CONTINUATION	$455,856
														Subtotal = $455,856

Issue Date FY: 2021 ( Subtotal = $465,158 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	2	6/22/2021	NON-COMPETING CONTINUATION	$465,158
														Subtotal = $465,158

Issue Date FY: 2020 ( Subtotal = $463,725 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	3/26/2020	NEW	$463,725
														Subtotal = $463,725

Grand Total All Awards = $2,282,494

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Branched chain amino acids and pancreatic cancer

Award Number: R01CA248315

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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