Tumor-penetrating therapy for β5 integrin-rich pancreas cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue. Here, we report that carcinoma-associated fibroblasts (CAFs) induce beta 5 integrin expression in tumor cells in a TGF-beta dependent manner, making them an efficient drug delivery target for the tumor-penetrating peptide iRGD. The capacity of iRGD to deliver conjugated and co-injected payloads is markedly suppressed when beta 5 integrins are knocked out in the tumor cells. Of note, beta 5 integrin knock-out in tumor cells leads to reduced disease burden and prolonged survival of the mice, demonstrating its contribution to PDAC progression. iRGD significantly potentiates co-injected chemotherapy in KPC mice with high beta 5 integrin expression and may be a powerful strategy to target an aggressive PDAC subpopulation. The iRGD tumor-penetrating peptide can achieve tumor specific drug delivery but whether and how it can penetrate into desmoplastic tumors is unknown. Here, the authors show that beta 5 integrin expression on tumor cells, mediated by CAFs-derived TGF-beta, is required for iRGD penetration into the desmoplastic PDAC microenvironment and that iRGD-based combination therapy is effective in PDAC mouse models.