Activation of the phosphoinositide-3-kinase and mammalian target of rapamycin signaling pathways are associated with shortened survival in patients with malignant peritoneal mesothelioma.
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.
Varghese
Sheelu
S
Division of Surgical Oncology, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Chen
Zhaorong
Z
Bartlett
David L
DL
Pingpank
James F
JF
Libutti
Steven K
SK
Steinberg
Seth M
SM
Wunderlich
John
J
Alexander
H Richard
HR
D000293:Adolescent; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000378:metabolism* / Q000401:mortality*; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000401:mortality*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000081082:Phosphoinositide-3 Kinase Inhibitors; C546842:MTOR protein, human; D058543:Class Ia Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases