Abstract LB012: Claudin-1 is a driver and therapeutic target for cholangiocarcinoma

Abstract Introduction: Cholangiocarcinoma (CCA) shows an alarming rise in incidence and mortality with unsatisfactory treatment options. Claudin-1 (CLDN1), a member of the tight junction family, is a transmembrane protein mediating cell stemness, plasticity and signaling. The functional role of CLDN1 as a therapeutic target for CCA is unknown. We have previously developed highly specific monoclonal antibodies (mAb) targeting exposed non-junctional CLDN1 exhibiting an excellent safety profile in non-human primates (Roehlen, Saviano et al. Science Translational Medicine 2022). Here, we aimed to explore the role of CLDN1 as an oncogenic driver and therapeutic target for CCA. Methods: Comprehensive CLDN1 expression analyses in patient tissues were performed to evaluate CLDN1 as a therapeutic target. Proof-of-concept studies using CLDN1 mAbs were performed in state-of-the-art mouse CDX and PDX models including models for advanced metastatic disease. Single-cell RNA sequencing and proteomics were applied to investigate tumor cell fate and signaling in vivo and ex vivo models. Results: Comprehensive analyses of CLDN1 protein and RNA expression in CCA patient tissues revealed a marked and significant upregulation of CLDN1 in CCA. Single-cell RNA sequencing of the CCA microenvironment revealed strong expression in tumor cells showing EMT, cell cycle and interferon response signature, uncovering CLDN1 as a therapeutic target. Targeting exposed CLDN1 by highly specific mAbs resulted in a significant and robust antitumoral effect in vivo across CDX and PDX models for intra- and extrahepatic CCA including advanced metastatic disease. Functional studies in cell-based models of CCA showed that CLDN1 mAbs markedly and significantly suppressed migration and invasion of tumor cells. Mechanistically, treatment with CLDN1 mAb suppressed Notch1, Src, and Hippo-YAP signaling - key signal transduction pathways implicated in CCA development and progression. Conclusion: Collectively, these results support an important functional role for CLDN1 in CCA pathogenesis and provide robust pre-clinical proof-of-concept for CLDN1-specific mAbs to treat CCA, setting the stage for its clinical development. Citation Format: Marion Muller, Zeina Nehme, Emilie Crouchet, Frank Jühling, Natascha Röhlen, Patrick Pessaux, Emanuele Felli, Lipika Goyal, Markus Meyer, Roberto Iacone, Alberto Toso, Luigi Manenti, Patrice Laquerriere, Aïna Venkatasamy, Nabeel Bardeesy, Catherine Schuster, Laurent Mailly, Thomas F. Baumert. Claudin-1 is a driver and therapeutic target for cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB012.