Activation of mTOR in a subgroup of ovarian carcinomas: correlation with p-eIF-4E and prognosis.
Ovarian carcinoma patients have an extremely poor prognosis; therefore, new molecular therapeutic approaches are urgently needed. The mTOR pathway, which may be targeted by substances such as Rapamycin or RAD001, is emerging as a promising target for anticancer therapy. So far, the expression and prognostic impact of mTOR signalling elements have not been completely studied in ovarian tumors. We analyzed p-mTOR, p-4E-BP1 and p-eIF-4E in 107 human ovarian lesions and observed an overexpression of p-mTOR (47%) and p-eIF-4E (56%) protein in primary ovarian carcinomas as compared to borderline tumors. Phospho-mTOR expression was significantly related to p-eIF-4E (p< or =0.001) and serous histological type (p=0.03). Increased p-4E-BP1 (31%) was associated with poor differentiation (p=0.04) and higher mitotic rate (p=0.004). In univariate analysis, increased expression of p-mTOR and p-eIF-4E was significantly associated with better overall survival (p=0.003, p=0.029). To connect the expression data with mechanistic studies, a set of 10 ovarian cancer cell lines was used. Expression of p-mTOR was increased in all cancer cell lines as compared to ovarian surface epithelial (HOSE) cells. Rapamycin treatment revealed a reduction of p-mTOR and p-4E-BP1 but increased p-AKT levels. We show for the first time an association of p-mTOR and p-eIF-4E with better overall survival for ovarian cancer patients. The combined results of our in vivo and cell culture studies suggest that a subpopulation of these patients may benefit from mTOR inhibition. The design of future clinical trials should incorporate biomarker testing to determine predictive markers for response to mTOR inhibitors.
Noske
Aurelia
A
Institute of Pathology, Charité University Hospital, Campus Mitte, D-10117 Berlin, Germany. aurelia.noske@charite.de
Lindenberg
Juliane Lena
JL
Darb-Esfahani
Silvia
S
Weichert
Wilko
W
Buckendahl
Ann-Christin
AC
Röske
Annika
A
Sehouli
Jalid
J
Dietel
Manfred
M
Denkert
Carsten
C
D000368:Aged; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D039561:Eukaryotic Initiation Factor-4E / Q000096:biosynthesis* / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D008938:Mitosis; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011379:Prognosis; D011494:Protein Kinases / Q000096:biosynthesis* / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D039561:Eukaryotic Initiation Factor-4E; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases