Engineered cyclic peptide targeting ITGA5 disrupts tumor–stroma interaction to overcome desmoplasia and resistance in pancreatic ductal adenocarcinoma

Acta Pharmaceutica Sinica B, vol. 16, pp. 305–321

Abstract

The tumor-stroma interaction contributes to the aggressive and resistance nature of pancreatic ductal adenocarcinoma (PDAC), leading to treatment failure. Cancer-associated fibroblasts (CAFs), a key cell type in the stroma, produce abundant extracellular matrix (ECM) and exhibit crosstalk with cancer cells inducing chemoresistance. In this study, we designed a cyclic peptide (cyAV3.3) targeting integrin α 5 (ITGA5) to disrupt CAF-induced desmoplasia and crosstalk with cancer cells. In vitro , cyAV3.3 inhibited the differentiation of pancreatic stellate cells into CAFs and reduced ECM production. In 3D co-cultured human spheroid models, the peptide decreased markers of resistance (ABCG1, BCL2, CXCR4), stemness (WNT1, CD44) and ECM remodeling (COL1A1, MMP2/9, LOX) and enhanced gemcitabine efficacy. In vivo , radiolabeled cyAV3.3 exhibited high tumor accumulation and retention following parenteral injections in a co-injection xenograft tumor model. Intriguingly, combination of cyAV3.3 with gemcitabine resulted in improved therapeutic efficacy of gemcitabine in co-injection xenograft and genetically engineered LSL-Kras G12D/+ LSL-Trp53 R172H/+ Pdx1-Cre (KPC) PDAC models. These effects were attributed to reduced desmoplasia, vasculature compression and enhanced infiltration of cytotoxic T cells and apoptosis. This study presents a novel cyclic peptide inhibiting ITGA5-mediated tumor-stroma interaction and thereby reduce desmoplasia and resistance, ultimately enhancing chemotherapy efficacy in PDAC.

Authors 8

1. Deby Fajar Mardhian

   Padjadjaran University · University of Twente

   Affiliation as printed

   Department of Dental Materials and Technology, Faculty of Dentistry, Padjadjaran University, Bandung 40132, Indonesia

   Engineered Therapeutics Group, Department of Advanced Organ Bioengineering and Therapeutics, Faculty of Science and Technology, University of Twente, Enschede 7500AE, The Netherlands

2. Kunal P. Pednekar

   University of Twente

   Affiliation as printed

   Engineered Therapeutics Group, Department of Advanced Organ Bioengineering and Therapeutics, Faculty of Science and Technology, University of Twente, Enschede 7500AE, The Netherlands

3. Praneeth Reddy Kuninty

   University of Twente

   Affiliation as printed

   Engineered Therapeutics Group, Department of Advanced Organ Bioengineering and Therapeutics, Faculty of Science and Technology, University of Twente, Enschede 7500AE, The Netherlands

4. Saadia A. Karim

   Cancer Research UK Scotland Institute

   Affiliation as printed

   CRUK Scotland Institute, Glasgow G61 1BD, UK

5. S. Winter

   University of Twente

   Affiliation as printed

   Engineered Therapeutics Group, Department of Advanced Organ Bioengineering and Therapeutics, Faculty of Science and Technology, University of Twente, Enschede 7500AE, The Netherlands

6. Josbert M. Metselaar Aachen Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen 52074, Germany

   ScarTec Therapeutics BV, Horst 2, Enschede 7522LW, The Netherlands

7. Jennifer P. Morton

   Cancer Research UK Scotland Institute · University of Glasgow

   Affiliation as printed

   CRUK Scotland Institute, Glasgow G61 1BD, UK

   School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK

8. Jai Prakash corresponding

   Radboud University Nijmegen · Radboud University Medical Center · University of Twente

   Affiliation as printed

   Department of Medical Biosciences, Radboud University Medical Centre, Geert Grooteplein Zuid 10, Nijmegen 6525 GA, The Netherlands

   Engineered Therapeutics Group, Department of Advanced Organ Bioengineering and Therapeutics, Faculty of Science and Technology, University of Twente, Enschede 7500AE, The Netherlands

   ScarTec Therapeutics BV, Horst 2, Enschede 7522LW, The Netherlands