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Abstract Introduction: Cholangiocarcinoma (CCA) is a highly aggressive adenocarcinoma of the hepatobiliary system showing an alarming rise in incidence and mortality with unsatisfactory treatment options. Claudin-1 (CLDN1) is a transmembrane protein expressed in tight junctions, but exposed at the cell surface on cancer epithelial cells. Using highly specific monoclonal antibodies (mAbs) targeting the extracellular loop 1 of exposed CLDN1 with an excellent safety profile (Roehlen, Saviano et al. Science Transl Med 2022), we aimed to investigate the role of CLDN1 as therapeutic target for CCA. Methods: Integrative CCA patient CLDN1 expression analyses, spatial transcriptomics and mouse models were used to evaluate the role of CLDN1 as an oncogenic driver for CCA. Proof-of-concept studies were performed in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse as well as patient CCA organoid models using humanized CLDN1 mAbs. Results: Integrative expression analyses of CLDN1 in CCA patient tissues revealed robust CLDN1 upregulation across several cohorts and patients with well-characterized driver mutations. scRNASeq and spatial transcriptomics of patient CCA showed that CLDN1 expression in cancer cells is associated with stemness, oncogenic signaling and EMT. Gain-of-function studies using an orthotopic HDTVi and syngeneic mouse model revealed a decrease in survival and an enhanced tumor growth, unraveling a functional role of CLDN1 as an oncogenic driver in CCA. Targeting exposed CLDN1 using highly CLDN1-specific mAb demonstrated a robust anti-tumoral effect across intra- and extra-hepatic CCA mouse models, with a significant inhibition of metastatic disease including models with medium or low CLDN1 expression. Functional studies in patient-derived CCA organoids demonstrated that CLDN1 mAb decreased cellular viability and altered cancer cell plasticity and fate. Mechanistically, CLDN1 mAb treatment suppressed gene expression of pathways mediating proliferation, stemness and EMT by inhibition of Notch1, SRC-FAK, and Hippo-YAP signaling. Conclusion: These results demonstrate that CLDN1 is a CCA driver and therapeutic target. The proof-of-concept studies in patient-derived models pave the way for the clinical development of CLDN1 mAbs to improve the outcomes of patients with advanced CCA. Citation Format: Zeina Nehme, Marion Muller, Emilie Crouchet, Frank Juehling, Julien Moehlin, Romain Désert, Jade Brochon, Fabio Del Zompo, Natascha Roehlen, Christine Thumann, Patrick Pessaux, Emanuele Felli, Aïna Venkatasamy, Patrice Marchand, Mihaela Alina Onea, Roberto Iacone, Markus Meyer, Alberto Toso, Nabeel Bardeesy, Lipika Goyal, Vikas Prakash Ranvir, Mirian Fernández-Vaquero, Mathias Heikenwälder, Tessa Ostyn, Tania Roskams, Patrice Laquerriere, Catherine Schuster, Laurent Mailly, Thomas F. Baumert. Treatment of cholangiocarcinoma using humanized monoclonal antibodies targeting claudin-1 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5981.
Nehme et al. (Fri,) studied this question.