Tumor-penetrating stromal modification of β5 integrin-rich pancreatic cancer

The β5 integrin in the form of the αvβ5 heterodimer is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and serves as a predictor of poor survival in PDAC patients. Genetically deleting β5 integrin in PDAC cells greatly delays tumor growth and metastasis in mice. Our studies over the years revealed that αvβ5 integrin expression is induced by transforming growth factor (TGF)-β released by various cells in the PDAC tissue, and that the integrin serves as a major activator of TGF-β to allow PDAC to maintain an αvβ5- and TGF-β-rich tumor microenvironment (TME). This system likely promotes the desmoplastic, hypo-perfused, immunosuppressive, and metastatic nature of the disease as TGF-β is known to be one of the key inducers of these characteristic TME features. Our recent data show that the αvβ5-binding iRGD tumor-penetrating peptide effectively inhibits the αvβ5-mediated TGF-β activation widely in the tumor. Long-term therapy with iRGD appears to reduce the malignant TME features of PDAC leading to improved perfusion, CD8+ T cell infiltration, less stromal fibers, and strikingly reduced metastasis in PDAC mice. iRGD was originally developed as a drug delivery system that acutely induces vascular and tissue permeability in the tumor to enhance tumor- specific entry and efficacy of drugs. The new findings above suggest that iRGD also chronically modifies the TME, which may contribute to its ability to deliver and potentiate various therapies. Our recent work also revealed that iRGD preferentially targets and depletes regulatory T cells (Tregs) in mouse PDAC to expand CD8+ T cells because PDAC-infiltrating Tregs express the αvβ5 integrin perhaps as an activation marker. Likely as a result of these combined effects, iRGD sensitizes PDAC to anti-programmed cell death ligand 1 (PD-L1) therapy in PDAC mice. The ongoing iLSTA clinical trial that studies the safety and preliminary efficacy of iRGD along with gemcitabine, Nab-paclitaxel, and an anti-PD-L1 antibody (durvalumab) in PDAC patients is showing promise. Here, we will characterize the effects of iRGD on the PDAC TME to maximize the benefits of using iRGD as an adjunct for other therapies. The goal is to identify master regulators (MRs) of response and resistance to iRGD therapy to develop probes that help stratify patients to iRGD therapy and novel targets that would further improve the efficacy of iRGD therapy. To this end, we will analyze the phenotypic and functional changes of various PDAC components, such as blood vessels, immune cells, fibroblasts, cancer cells, and stromal fibers in response to iRGD at gene and protein levels using spatial transcriptomics, humanized PDAC mice, and clinical samples from the iLSTA trial. MRs of response will be validated as a predictor of positive outcome in PDAC patients. Inhibitors of the MRs of resistance will be tested in proof-of-principle treatment studies in mouse models to study if they outperform or enhance the efficacy of existing regimens. Project Number: 1R01CA307667-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Kazuki Sugahara (+1 co-PI) | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $683,970 | Activity Code: R01 | Study Section: Molecular Cancer Diagnosis and Classification Study Section[MCDC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11277133