CCK Receptor Inhibition Reduces Pancreatic Tumor Fibrosis and Promotes Nanoparticle Delivery
Thomas Abraham1, Michael Armold2, Christopher McGovern2
1Department of Neural and Behavioral Sciences, Penn State College of Medicine, P.O. Box 850, Hershey, PA 17036, USA.
Biomedicines
|May 25, 2024
Summary
Proglumide, a CCKR antagonist, reduces pancreatic tumor fibrosis, improving nanoparticle delivery. This drug normalizes the tumor microenvironment, enhancing therapeutic potential for pancreatic ductal adenocarcinoma (PDAC) patients.
Area of Science:
- Oncology
- Cancer Biology
- Nanomedicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to its fibrotic tumor microenvironment (TME).
- Tumor fibrosis impedes the delivery of therapeutics, including nanoparticles (NPs).
- Cholecystokinin receptor (CCKR) antagonists, like proglumide, have shown potential in reducing fibrosis.
Purpose of the Study:
- To investigate how proglumide reduces fibrosis in the PDAC TME.
- To determine the impact of proglumide-induced fibrosis reduction on nanoparticle uptake.
- To explore the role of CCK2 receptors on tumor cells in PDAC desmoplasia.
Main Methods:
- Orthotopic injection of PDAC cells in mice, followed by proglumide treatment.
- Ex vivo analysis of tumors for fibrosis, vascularity, stellate cell activation, and nanoparticle distribution.
- Assessment of CCK2 receptor knockdown effects on collagen reduction in PANC-1 cells.
Main Results:
- Proglumide treatment significantly reduced stromal collagen and decreased cancer-associated fibroblast (CAF) activation.
- Proglumide increased tumor vascularity and enhanced the intra-tumoral distribution of nanoparticles.
- CCK2 receptor knockdown in tumor cells further reduced collagen, confirming their role in desmoplasia.
Conclusions:
- CCK2 receptor blockade by proglumide exerts anti-fibrotic effects within the PDAC TME.
- Reduced fibrosis improves nanoparticle delivery, offering a strategy to enhance PDAC treatment.
- Proglumide demonstrates potential as an adjuvant therapy for improving nano-encapsulated therapeutic delivery in pancreatic cancer.
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