Activation of the phosphoinositide-3-kinase and mammalian target of rapamycin signaling pathways are associated with shortened survival in patients with malignant peritoneal mesothelioma

Authors

  • Sheelu Varghese PhD,

    1. Division of Surgical Oncology, Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland
    2. The Marlene and Stewart Greenebaum Cancer Center, The University of Maryland School of Medicine, Baltimore, Maryland
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  • Zhaorong Chen BS,

    1. Division of Surgical Oncology, Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland
    2. The Marlene and Stewart Greenebaum Cancer Center, The University of Maryland School of Medicine, Baltimore, Maryland
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  • David L. Bartlett MD,

    1. Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
    Current affiliation:
    1. Department of Surgery, Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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  • James F. Pingpank MD,

    1. Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
    Current affiliation:
    1. Department of Surgery, Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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  • Steven K. Libutti MD,

    1. Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
    Current affiliation:
    1. Department of Surgery, Montefiore Medical Center, Bronx, New York
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  • Seth M. Steinberg PhD,

    1. Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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  • John Wunderlich MD,

    1. Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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  • H. Richard Alexander Jr. MD

    Corresponding author
    1. Division of Surgical Oncology, Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland
    2. The Marlene and Stewart Greenebaum Cancer Center, The University of Maryland School of Medicine, Baltimore, Maryland
    • Department of Surgery, University of Maryland School of Medicine, 22 South Greene Street S4B05A, Baltimore, MD 21201
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    • Fax: (410) 328-5919


Abstract

BACKGROUND:

Malignant peritoneal mesothelioma (MPM) is a rare malignancy of the serosal membranes of the abdominal cavity. This cancer is ultimately fatal in almost all afflicted individuals; however, there is marked variability in its clinical behavior: Some patients die rapidly, and others survive for many years. In the current study, the authors investigated the molecular nature of MPM to obtain insights into the heterogeneity of its clinical behavior and to identify new therapeutic targets for intervention.

METHODS:

Fresh pretreatment tumor samples were collected from 41 patients with MPM who underwent surgical cytoreduction and received regional intraoperative chemotherapy perfusion. From those samples, gene expression analyses were performed. The major cellular pathways that were identified in this cancer were inhibited using a pathway-specific inhibitor.

RESULTS:

Unsupervised clustering of genes identified 2 distinct groups of patients with significantly different survivals (Group A: median survival, 24 months; Group B: median survival, 69.5 months; P = .035). Phosphoinositide-3-kinase (PI3K) and the closely interacting mammalian target of rapamycin (mTOR) signaling pathways were overexpressed predominantly in the poor survival group; and the genes of these pathways, phosphoinositide-3-kinase, catalytic, α polypeptide (PIK3CA) and rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR), were highly significantly predictive of shortened patient survival in Group A. The role of these pathways in MPM tumor progression was also investigated by treating 2 MPM cell lines with BEZ235, a dual-class PI3K and mTOR inhibitor, and the authors observed significant inhibition of downstream cell signaling and cell proliferation.

CONCLUSIONS:

Taken together, the results from this study revealed that, based on gene expression profiles, there were 2 distinct patient groups with significantly different survival and that targeting the PI3K and mTOR signaling pathways may have significant therapeutic value in patients with MPM. Cancer 2011. © 2010 American Cancer Society.

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