Document Detail


Activation of mTOR in a subgroup of ovarian carcinomas: correlation with p-eIF-4E and prognosis.
MedLine Citation:
PMID:  19020722     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Aurelia Noske; Juliane Lena Lindenberg; Silvia Darb-Esfahani; Wilko Weichert; Ann-Christin Buckendahl; Annika Röske; Jalid Sehouli; Manfred Dietel; Carsten Denkert
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Oncology reports     Volume:  20     ISSN:  1021-335X     ISO Abbreviation:  Oncol. Rep.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-21     Completed Date:  2009-02-04     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9422756     Medline TA:  Oncol Rep     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1409-17     Citation Subset:  IM    
Affiliation:
Institute of Pathology, Charité University Hospital, Campus Mitte, D-10117 Berlin, Germany. aurelia.noske@charite.de
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MeSH Terms
Descriptor/Qualifier:
Aged
Apoptosis
Cell Cycle
Cell Line, Tumor
Enzyme Activation
Eukaryotic Initiation Factor-4E / biosynthesis*,  physiology*
Female
Gene Expression Profiling
Humans
Immunohistochemistry / methods
Middle Aged
Mitosis
Ovarian Neoplasms / metabolism*
Prognosis
Protein Kinases / biosynthesis*,  physiology*
Chemical
Reg. No./Substance:
0/Eukaryotic Initiation Factor-4E; EC 2.7.-/Protein Kinases; EC 2.7.1.-/mTOR protein

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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