title: Immunotoxin targeting EpCAM effectively inhibits peritoneal tumor growth in experimental models of mucinous peritoneal surface malignancies.
abstract: Cytoreductive surgery and intraperitoneal (i.p.) chemotherapy constitute a curative treatment option in mucinous peritoneal surface malignancies of intestinal origin, but treatment outcome is highly variable and the search for novel therapies is warranted. Immunotoxins are attractive candidates for targeted therapy in the peritoneal cavity because of direct cytotoxicity, distinct mechanisms of action and tumor cell selectivity. The MOC31PE immunotoxin targets the tumor-associated adhesion protein EpCAM (Epithelial Cell Adhesion Molecule), and has been administered safely in early clinical trials. In our work, the efficacy of i.p. administration of MOC31PE alone and together with mitomycin C (MMC) was investigated in unique animal models of human mucinous peritoneal surface malignancies. In initial model validation experiments, clear differences in efficacy were demonstrated between MMC and oxaliplatin, favoring MMC in five investigated tumor models. Subsequently, MOC31PE and MMC were given as single i.p. injections alone and in combination. In the PMCA-2 model, moderate growth inhibition was obtained with both drugs, while the combination resulted in at least additive effects; whereas the PMP-2 model was highly sensitive to both drugs separately and in combination and intermediate sensitivity was found for the PMCA-3 model. Furthermore, results from ex vivo experiments on freshly obtained mucinous tumor tissue from animals and patients suggested that classic mechanisms of immunotoxin activity were involved, i.e., inhibition of protein synthesis and induction of apoptosis. The present results suggest that adding MOC31PE to MMC-based i.p. chemotherapy should be further explored for EpCAM-expressing peritoneal surface malignancies, and a phase I trial is in preparation.
authors.affiliation: Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway. kjersti.flatmark@rr-research.no
authors.forename: Kjersti
authors.initials: K
authors.lastname: Flatmark
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Guldvik
authors.forename: Hege
authors.initials: H
authors.lastname: Svensson
authors.forename: Karianne G
authors.initials: KG
authors.lastname: Fleten
authors.forename: Vivi Ann
authors.initials: VA
authors.lastname: Flørenes
authors.forename: Wenche
authors.initials: W
authors.lastname: Reed
authors.forename: Karl-Erik
authors.initials: KE
authors.lastname: Giercksky
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Fodstad
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Andersson
mesh_terms: D036002:ADP Ribose Transferases / Q000627:therapeutic use*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001427:Bacterial Toxins / Q000627:therapeutic use*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D004195:Disease Models, Animal; D000071858:Epithelial Cell Adhesion Molecule; D005098:Exotoxins / Q000627:therapeutic use*; D005260:Female; D000922:Immunotoxins / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin / Q000627:therapeutic use; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D037521:Virulence Factors / Q000627:therapeutic use*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000951:Antigens, Neoplasm; D001427:Bacterial Toxins; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D005098:Exotoxins; D000922:Immunotoxins; D016685:Mitomycin; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
keywords: EpCAM; MOC31PE; animal models; immunotoxin; mitomycin C; mucinous peritoneal surface malignancies; oxaliplatin