Immunotoxin targeting EpCAM effectively inhibits peritoneal tumor growth in experimental models of mucinous peritoneal surface malignancies

Authors

  • Kjersti Flatmark,

    Corresponding author
    1. Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
    • Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
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  • Ingrid J. Guldvik,

    1. Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
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  • Hege Svensson,

    1. Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
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  • Karianne G. Fleten,

    1. Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
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  • Vivi Ann Flørenes,

    1. Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
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  • Wenche Reed,

    1. Research Innovation and Education, Oslo University Hospital, Oslo, Norway
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  • Karl-Erik Giercksky,

    1. Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
    2. University of Oslo, Institute of Clinical Medicine, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
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  • Øystein Fodstad,

    1. Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
    2. University of Oslo, Institute of Clinical Medicine, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
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  • Yvonne Andersson

    1. Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
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  • Conflict of interest: None

Correspondence to: Kjersti Flatmark, Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0310 Oslo, Norway, Tel.: +47–22934000, Fax: +47–22781895, E-mail: kjersti.flatmark@rr-research.no

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.

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