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CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy

The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular prot...

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Autores principales: Resovi, Andrea, Borsotti, Patrizia, Ceruti, Tommaso, Passoni, Alice, Zucchetti, Massimo, Berndt, Alexander, Riser, Bruce L., Taraboletti, Giulia, Belotti, Dorina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226963/
https://www.ncbi.nlm.nih.gov/pubmed/32294968
http://dx.doi.org/10.3390/cells9040952
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author Resovi, Andrea
Borsotti, Patrizia
Ceruti, Tommaso
Passoni, Alice
Zucchetti, Massimo
Berndt, Alexander
Riser, Bruce L.
Taraboletti, Giulia
Belotti, Dorina
author_facet Resovi, Andrea
Borsotti, Patrizia
Ceruti, Tommaso
Passoni, Alice
Zucchetti, Massimo
Berndt, Alexander
Riser, Bruce L.
Taraboletti, Giulia
Belotti, Dorina
author_sort Resovi, Andrea
collection PubMed
description The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular protein, highly present in the PDAC microenvironment and associated with disease progression. Here we have investigated the therapeutic value of the CCN2-targeting BLR100 and BLR200, two modified synthetic peptides derived from active regions of CCN3, an endogenous inhibitor of CCN2. In a murine orthotopic PDAC model, the two peptides, administered as monotherapy at low doses (approximating physiological levels of CCN3), had tumor inhibitory activity that increased with the dose. The peptides affected the tumor microenvironment, inhibiting fibrosis and vessel formation and reducing necrosis. Both peptides were active in preventing ascites formation. An increased activity was obtained in combination regimens, administering BLR100 or BLR200 with the chemotherapeutic drug gemcitabine. Pharmacokinetic analysis indicated that the improved activity of the combination was not mainly determined by the substantial increase in gemcitabine delivery to tumors, suggesting other effects on the tumor microenvironment. The beneficial remodeling of the tumor stroma supports the potential value of these CCN3-derived peptides for targeting pathways regulated by CCN2 in PDAC.
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spelling pubmed-72269632020-05-18 CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy Resovi, Andrea Borsotti, Patrizia Ceruti, Tommaso Passoni, Alice Zucchetti, Massimo Berndt, Alexander Riser, Bruce L. Taraboletti, Giulia Belotti, Dorina Cells Article The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular protein, highly present in the PDAC microenvironment and associated with disease progression. Here we have investigated the therapeutic value of the CCN2-targeting BLR100 and BLR200, two modified synthetic peptides derived from active regions of CCN3, an endogenous inhibitor of CCN2. In a murine orthotopic PDAC model, the two peptides, administered as monotherapy at low doses (approximating physiological levels of CCN3), had tumor inhibitory activity that increased with the dose. The peptides affected the tumor microenvironment, inhibiting fibrosis and vessel formation and reducing necrosis. Both peptides were active in preventing ascites formation. An increased activity was obtained in combination regimens, administering BLR100 or BLR200 with the chemotherapeutic drug gemcitabine. Pharmacokinetic analysis indicated that the improved activity of the combination was not mainly determined by the substantial increase in gemcitabine delivery to tumors, suggesting other effects on the tumor microenvironment. The beneficial remodeling of the tumor stroma supports the potential value of these CCN3-derived peptides for targeting pathways regulated by CCN2 in PDAC. MDPI 2020-04-13 /pmc/articles/PMC7226963/ /pubmed/32294968 http://dx.doi.org/10.3390/cells9040952 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Resovi, Andrea
Borsotti, Patrizia
Ceruti, Tommaso
Passoni, Alice
Zucchetti, Massimo
Berndt, Alexander
Riser, Bruce L.
Taraboletti, Giulia
Belotti, Dorina
CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy
title CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy
title_full CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy
title_fullStr CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy
title_full_unstemmed CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy
title_short CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy
title_sort ccn-based therapeutic peptides modify pancreatic ductal adenocarcinoma microenvironment and decrease tumor growth in combination with chemotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226963/
https://www.ncbi.nlm.nih.gov/pubmed/32294968
http://dx.doi.org/10.3390/cells9040952
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