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The CCK-B receptor signaling pathway as a driver of pancreatic cellular plasticity and carcinogenesis

Award Number: R01CA277680
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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The CCK-B receptor signaling pathway as a driver of pancreatic cellular plasticity and carcinogenesis - Abstract It has become well recognized that inflammation from chronic pancreatitis is associated an 8-fold increased risk for the development of pancreatic cancer. When cells are injured or stressed, they can transform to a cell with a different phenotype through a process called metaplasia. In the pancreas, acinar-ductal metaplasia (ADM) occurs with pancreatitis and this process is usually reversible. However, with chronic inflammation or maturation arrest, the ductal phenotype cells do not reverse to their normal acinar phenotype but may progress to pancreatic intraepithelial neoplasia (PanINs) and pancreatic cancer. There is a gap in our understanding of the mechanisms involved in this recovery or loss of the ability to recover. Our lab has been studying G-protein coupled receptors and found that the cholecystokinin-B receptor (CCK-BR) that is found in ductal cells but not acinar cells becomes expressed during chronic pancreatitis and PanIN formation, and is markedly over-expressed in pancreatic cancer. Treatment with a CCK-receptor antagonist, proglumide, hastens recovery of ADM, decreases inflammation, and restores the pancreas to a normal phenotype. In more advanced disease with PanINs or with pancreatic cancer, proglumide treatment also alters the pancreas extracellular matrix or tumor microenvironment, by decreasing collagen production from pancreatic stellate cells or cancer-associated fibroblasts and changing the immune cell signature to a more normal phenotype. We hypothesize that the CCK-BR signaling pathway is a novel and key pathway in pancreatic plasticity; strategies to suppress this pathway will decrease pancreatic cancer. Proglumide has already been tested in human subjects in a Phase 1 clinical trial and deemed to have a broad safety profile. In this proposal we will study the role of proglumide and the CCK-BR in pancreatic cell plasticity and how this pathway can be targeted to normalize the pancreatic phenotype and render it less oncogenic to prevent pancreatic cancer. The following aims are proposed: Aim #1, Determine how the CCK-BR signaling pathway is involved in acinar-ductal metaplasia; Aim #2, Examine how activation of the CCK-B receptor pathway modulates pancreatic stellate cells and if CCK- receptor blockade can change the phenotype to render the fibroblasts less carcinogenic; and Aim #3, Evaluate how activation of the CCK-BR induces tissue inflammation and polarization of immune cells. In this investigation, we will use murine models of pancreatitis in wild-type and in CCK-BR-knockout mice with state of the art techniques as laser microdissection of ADM and stroma, Reverse phase protein array, Mass Cytometry and RNA sequencing to understand plasticity of pancreatic cells. We will also examine the role of the CCK-BR on the pancreatic stellate cells in vitro using murine and human cells. Our goal is to understand how proglumide reprograms a metaplastic or dysplastic pancreas to a more normal phenotype and thus preventing development of 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 = $630,603 )
2026	2026	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	4	3/23/2026	NON-COMPETING CONTINUATION	$630,603
														Subtotal = $630,603

Issue Date FY: 2025 ( Subtotal = $630,773 )
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	3	2/28/2025	NON-COMPETING CONTINUATION	$567,696
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$63,077
														Subtotal = $630,773

Issue Date FY: 2024 ( Subtotal = $562,784 )
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	2	3/4/2024	NON-COMPETING CONTINUATION	$533,164
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	001	2	4/18/2024	NON-COMPETING CONTINUATION	$29,620
														Subtotal = $562,784

Issue Date FY: 2023 ( Subtotal = $606,404 )
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	1	2/22/2023	NEW	$606,404
														Subtotal = $606,404

Grand Total All Awards = $2,430,564

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The CCK-B receptor signaling pathway as a driver of pancreatic cellular plasticity and carcinogenesis

Award Number: R01CA277680

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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