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

Sheelu Varghese, Zhaorong Chen, David L. Bartlett, James F. Pingpank, Steven K. Libutti, Seth M. Steinberg, John Wunderlich, H. Richard Alexander

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)361-371
Number of pages11
JournalCancer
Volume117
Issue number2
DOIs
StatePublished - Jan 15 2011

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1-Phosphatidylinositol 4-Kinase
Sirolimus
Survival
Neoplasms
Abdominal Cavity
Transcriptome
Genes
Cluster Analysis
Malignant Mesothelioma
Perfusion
Cell Proliferation
Gene Expression
Drug Therapy
Cell Line
Peptides
Membranes
Therapeutics

Keywords

  • cancer pathways
  • microarray
  • patient survival
  • peritoneal mesothelioma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of the phosphoinositide-3-kinase and mammalian target of rapamycin signaling pathways are associated with shortened survival in patients with malignant peritoneal mesothelioma. / Varghese, Sheelu; Chen, Zhaorong; Bartlett, David L.; Pingpank, James F.; Libutti, Steven K.; Steinberg, Seth M.; Wunderlich, John; Alexander, H. Richard.

In: Cancer, Vol. 117, No. 2, 15.01.2011, p. 361-371.

Research output: Contribution to journalArticle

Varghese, Sheelu ; Chen, Zhaorong ; Bartlett, David L. ; Pingpank, James F. ; Libutti, Steven K. ; Steinberg, Seth M. ; Wunderlich, John ; Alexander, H. Richard. / Activation of the phosphoinositide-3-kinase and mammalian target of rapamycin signaling pathways are associated with shortened survival in patients with malignant peritoneal mesothelioma. In: Cancer. 2011 ; Vol. 117, No. 2. pp. 361-371.
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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.",
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AU - Bartlett, David L.

AU - Pingpank, James F.

AU - Libutti, Steven K.

AU - Steinberg, Seth M.

AU - Wunderlich, John

AU - Alexander, H. Richard

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AB - 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.

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