MSC-Delivered Soluble TRAIL and Paclitaxel as Novel Combinatory Treatment for Pancreatic Adenocarcinoma

Filippo Rossignoli; Carlotta Spano; Giulia Grisendi; Elisabetta Manuela Foppiani; Giulia Golinelli; Ilenia Mastrolia; Marco Bestagno; Olivia Candini; Tiziana Petrachi; Alessandra Recchia; Francesca Miselli; Giulia Rovesti; Giulia Orsi; Elena Veronesi; Gregorio Medici; Benedetta Petocchi; Massimo Pinelli; Edwin M Horwitz; Pierfranco Conte; Massimo Dominici

doi:10.7150/thno.27576

MSC-Delivered Soluble TRAIL and Paclitaxel as Novel Combinatory Treatment for Pancreatic Adenocarcinoma

Filippo Rossignoli, Carlotta Spano, Giulia Grisendi, Elisabetta Manuela Foppiani, Giulia Golinelli, Ilenia Mastrolia, Marco Bestagno, Olivia Candini, Tiziana Petrachi, Alessandra Recchia, Francesca Miselli, Giulia Rovesti, Giulia Orsi, Elena Veronesi, Gregorio Medici, Benedetta Petocchi, Massimo Pinelli, Edwin M Horwitz, Pierfranco Conte, Massimo Dominici

Istituto Oncologico Veneto

Research output: Contribution to journal › Article › peer-review

Abstract

Pancreatic cancer is the fourth leading cause of cancer death in western countries with more than 100,000 new cases per year in Europe and a mortality rate higher than 90%. In this scenario, advanced therapies based on gene therapies are emerging, thanks to a better understanding of tumour architecture and cancer cell alterations. We have demonstrated the efficacy of an innovative approach for pancreatic cancer based on mesenchymal stromal cells (MSC) genetically engineered to produce TNF-related Apoptosis Inducing Ligand (TRAIL). Here we investigated the combination of this MSC-based approach with the administration of a paclitaxel (PTX)-based chemotherapy to improve the potential of the treatment, also accounting for a possible resistance onset. Methods: Starting from the BXPC3 cell line, we generated and profiled a TRAIL-resistant model of pancreatic cancer, testing the impact of the combined treatment in vitro with specific cytotoxicity and metabolic assays. We then challenged the rationale in a subcutaneous mouse model of pancreatic cancer, assessing its effect on tumour size accounting stromal and parenchymal organization. Results: PTX was able to restore pancreatic cancer sensitivity to MSC-delivered TRAIL by reverting its pro-survival gene expression profile. The two compounds cooperate both in vitro and in vivo and the combined treatment resulted in an improved cytotoxicity on tumour cells. Conclusion: In summary, this study uncovers the potential of a combinatory approach between MSC-delivered TRAIL and PTX, supporting the combination of cell-based products and conventional chemotherapeutics as a tool to improve the efficacy of the treatments, also addressing possible mechanisms of resistance.

Original language	English
Pages (from-to)	436-448
Number of pages	13
Journal	Theranostics
Volume	9
Issue number	2
DOIs	https://doi.org/10.7150/thno.27576
Publication status	Published - Jan 1 2019

Keywords

Adenocarcinoma/therapy
Animals
Antineoplastic Agents/administration & dosage
Cell Line, Tumor
Cell- and Tissue-Based Therapy/methods
Combined Modality Therapy/methods
Disease Models, Animal
Humans
Mesenchymal Stem Cells/metabolism
Mice, Nude
Models, Theoretical
Neoplasm Transplantation
Paclitaxel/administration & dosage
Pancreatic Neoplasms/therapy
TNF-Related Apoptosis-Inducing Ligand/metabolism
Transplantation, Heterologous
Treatment Outcome

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Rossignoli, F., Spano, C., Grisendi, G., Foppiani, E. M., Golinelli, G., Mastrolia, I., Bestagno, M., Candini, O., Petrachi, T., Recchia, A., Miselli, F., Rovesti, G., Orsi, G., Veronesi, E., Medici, G., Petocchi, B., Pinelli, M., Horwitz, E. M., Conte, P., & Dominici, M. (2019). MSC-Delivered Soluble TRAIL and Paclitaxel as Novel Combinatory Treatment for Pancreatic Adenocarcinoma. Theranostics, 9(2), 436-448. https://doi.org/10.7150/thno.27576

Rossignoli, F, Spano, C, Grisendi, G, Foppiani, EM, Golinelli, G, Mastrolia, I, Bestagno, M, Candini, O, Petrachi, T, Recchia, A, Miselli, F, Rovesti, G, Orsi, G, Veronesi, E, Medici, G, Petocchi, B, Pinelli, M, Horwitz, EM, Conte, P & Dominici, M 2019, 'MSC-Delivered Soluble TRAIL and Paclitaxel as Novel Combinatory Treatment for Pancreatic Adenocarcinoma', Theranostics, vol. 9, no. 2, pp. 436-448. https://doi.org/10.7150/thno.27576

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title = "MSC-Delivered Soluble TRAIL and Paclitaxel as Novel Combinatory Treatment for Pancreatic Adenocarcinoma",

abstract = "Pancreatic cancer is the fourth leading cause of cancer death in western countries with more than 100,000 new cases per year in Europe and a mortality rate higher than 90%. In this scenario, advanced therapies based on gene therapies are emerging, thanks to a better understanding of tumour architecture and cancer cell alterations. We have demonstrated the efficacy of an innovative approach for pancreatic cancer based on mesenchymal stromal cells (MSC) genetically engineered to produce TNF-related Apoptosis Inducing Ligand (TRAIL). Here we investigated the combination of this MSC-based approach with the administration of a paclitaxel (PTX)-based chemotherapy to improve the potential of the treatment, also accounting for a possible resistance onset. Methods: Starting from the BXPC3 cell line, we generated and profiled a TRAIL-resistant model of pancreatic cancer, testing the impact of the combined treatment in vitro with specific cytotoxicity and metabolic assays. We then challenged the rationale in a subcutaneous mouse model of pancreatic cancer, assessing its effect on tumour size accounting stromal and parenchymal organization. Results: PTX was able to restore pancreatic cancer sensitivity to MSC-delivered TRAIL by reverting its pro-survival gene expression profile. The two compounds cooperate both in vitro and in vivo and the combined treatment resulted in an improved cytotoxicity on tumour cells. Conclusion: In summary, this study uncovers the potential of a combinatory approach between MSC-delivered TRAIL and PTX, supporting the combination of cell-based products and conventional chemotherapeutics as a tool to improve the efficacy of the treatments, also addressing possible mechanisms of resistance.",

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author = "Filippo Rossignoli and Carlotta Spano and Giulia Grisendi and Foppiani, {Elisabetta Manuela} and Giulia Golinelli and Ilenia Mastrolia and Marco Bestagno and Olivia Candini and Tiziana Petrachi and Alessandra Recchia and Francesca Miselli and Giulia Rovesti and Giulia Orsi and Elena Veronesi and Gregorio Medici and Benedetta Petocchi and Massimo Pinelli and Horwitz, {Edwin M} and Pierfranco Conte and Massimo Dominici",

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doi = "10.7150/thno.27576",

language = "English",

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pages = "436--448",

journal = "Theranostics",

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T1 - MSC-Delivered Soluble TRAIL and Paclitaxel as Novel Combinatory Treatment for Pancreatic Adenocarcinoma

AU - Rossignoli, Filippo

AU - Spano, Carlotta

AU - Grisendi, Giulia

AU - Foppiani, Elisabetta Manuela

AU - Golinelli, Giulia

AU - Mastrolia, Ilenia

AU - Bestagno, Marco

AU - Candini, Olivia

AU - Petrachi, Tiziana

AU - Recchia, Alessandra

AU - Miselli, Francesca

AU - Rovesti, Giulia

AU - Orsi, Giulia

AU - Veronesi, Elena

AU - Medici, Gregorio

AU - Petocchi, Benedetta

AU - Pinelli, Massimo

AU - Horwitz, Edwin M

AU - Conte, Pierfranco

AU - Dominici, Massimo

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Pancreatic cancer is the fourth leading cause of cancer death in western countries with more than 100,000 new cases per year in Europe and a mortality rate higher than 90%. In this scenario, advanced therapies based on gene therapies are emerging, thanks to a better understanding of tumour architecture and cancer cell alterations. We have demonstrated the efficacy of an innovative approach for pancreatic cancer based on mesenchymal stromal cells (MSC) genetically engineered to produce TNF-related Apoptosis Inducing Ligand (TRAIL). Here we investigated the combination of this MSC-based approach with the administration of a paclitaxel (PTX)-based chemotherapy to improve the potential of the treatment, also accounting for a possible resistance onset. Methods: Starting from the BXPC3 cell line, we generated and profiled a TRAIL-resistant model of pancreatic cancer, testing the impact of the combined treatment in vitro with specific cytotoxicity and metabolic assays. We then challenged the rationale in a subcutaneous mouse model of pancreatic cancer, assessing its effect on tumour size accounting stromal and parenchymal organization. Results: PTX was able to restore pancreatic cancer sensitivity to MSC-delivered TRAIL by reverting its pro-survival gene expression profile. The two compounds cooperate both in vitro and in vivo and the combined treatment resulted in an improved cytotoxicity on tumour cells. Conclusion: In summary, this study uncovers the potential of a combinatory approach between MSC-delivered TRAIL and PTX, supporting the combination of cell-based products and conventional chemotherapeutics as a tool to improve the efficacy of the treatments, also addressing possible mechanisms of resistance.

AB - Pancreatic cancer is the fourth leading cause of cancer death in western countries with more than 100,000 new cases per year in Europe and a mortality rate higher than 90%. In this scenario, advanced therapies based on gene therapies are emerging, thanks to a better understanding of tumour architecture and cancer cell alterations. We have demonstrated the efficacy of an innovative approach for pancreatic cancer based on mesenchymal stromal cells (MSC) genetically engineered to produce TNF-related Apoptosis Inducing Ligand (TRAIL). Here we investigated the combination of this MSC-based approach with the administration of a paclitaxel (PTX)-based chemotherapy to improve the potential of the treatment, also accounting for a possible resistance onset. Methods: Starting from the BXPC3 cell line, we generated and profiled a TRAIL-resistant model of pancreatic cancer, testing the impact of the combined treatment in vitro with specific cytotoxicity and metabolic assays. We then challenged the rationale in a subcutaneous mouse model of pancreatic cancer, assessing its effect on tumour size accounting stromal and parenchymal organization. Results: PTX was able to restore pancreatic cancer sensitivity to MSC-delivered TRAIL by reverting its pro-survival gene expression profile. The two compounds cooperate both in vitro and in vivo and the combined treatment resulted in an improved cytotoxicity on tumour cells. Conclusion: In summary, this study uncovers the potential of a combinatory approach between MSC-delivered TRAIL and PTX, supporting the combination of cell-based products and conventional chemotherapeutics as a tool to improve the efficacy of the treatments, also addressing possible mechanisms of resistance.

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KW - Animals

KW - Antineoplastic Agents/administration & dosage

KW - Cell Line, Tumor

KW - Cell- and Tissue-Based Therapy/methods

KW - Combined Modality Therapy/methods

KW - Disease Models, Animal

KW - Humans

KW - Mesenchymal Stem Cells/metabolism

KW - Mice, Nude

KW - Models, Theoretical

KW - Neoplasm Transplantation

KW - Paclitaxel/administration & dosage

KW - Pancreatic Neoplasms/therapy

KW - TNF-Related Apoptosis-Inducing Ligand/metabolism

KW - Transplantation, Heterologous

KW - Treatment Outcome

U2 - 10.7150/thno.27576

DO - 10.7150/thno.27576

M3 - Article

C2 - 30809285

SN - 1838-7640

VL - 9

SP - 436

EP - 448

JO - Theranostics

JF - Theranostics

IS - 2

ER -

MSC-Delivered Soluble TRAIL and Paclitaxel as Novel Combinatory Treatment for Pancreatic Adenocarcinoma

Abstract

Keywords

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