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

## TL;DR

A cyclic peptide targeting ITGA5 disrupts tumor-stroma interactions in pancreatic cancer, reducing resistance and improving chemotherapy effectiveness.

## Contribution

A novel cyclic peptide (cyAV3.3) is developed to target ITGA5 and disrupt tumor-stroma interactions in pancreatic cancer.

## Key findings

- cyAV3.3 inhibits pancreatic stellate cell differentiation into CAFs and reduces ECM production.
- The peptide enhances gemcitabine efficacy by reducing resistance and stemness markers in 3D models.
- In vivo, cyAV3.3 combined with gemcitabine improves therapeutic outcomes in PDAC models.

## 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 α5 (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-KrasG12D/+LSL-Trp53R172H/+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.

Engineered cyclic peptidomimetic inhibits activation of cancer-associated fibroblasts by targeting ITGA5/FAK axis, leading to reduced desmoplasia. This also inhibits tumor–stroma interaction, reducing stemness and resistance and increasing chemotherapy efficacy.Image 1