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Published on: August 2, 2024
Activation of mTOR in a subgroup of ovarian carcinomas: correlation with p-eIF-4E and prognosis
Aurelia Noske1, Juliane Lena Lindenberg, Silvia Darb-Esfahani
1Institute of Pathology, Charité University Hospital, Campus Mitte, D-10117 Berlin, Germany. aurelia.noske@charite.de
Abstract:
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.
Insights
New research shows that increased expression of mTOR pathway proteins, specifically phospho-mTOR (p-mTOR) and phospho-eIF-4E (p-eIF-4E), is linked to better survival in ovarian cancer patients. This suggests potential benefits from mTOR inhibitors for a subset of patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ovarian carcinoma has a poor prognosis, necessitating novel molecular therapies.
- The mTOR pathway is a promising anticancer target, but its role in ovarian tumors requires further investigation.
Purpose of the Study:
- To investigate the expression and prognostic significance of mTOR signaling elements (p-mTOR, p-4E-BP1, p-eIF-4E) in ovarian lesions.
- To explore the mechanistic effects of mTOR inhibition in ovarian cancer cell lines.
Main Methods:
- Analysis of p-mTOR, p-4E-BP1, and p-eIF-4E protein expression in 107 human ovarian lesions.
- Assessment of correlations between protein expression, clinicopathological features, and patient survival.
- In vitro studies using 10 ovarian cancer cell lines treated with Rapamycin.
Main Results:
- Overexpression of p-mTOR (47%) and p-eIF-4E (56%) was observed in primary ovarian carcinomas compared to borderline tumors.
- Increased p-mTOR correlated with p-eIF-4E and serous histological type.
- Elevated p-4E-BP1 was associated with poor differentiation and higher mitotic rate.
- Higher expression of p-mTOR and p-eIF-4E significantly correlated with better overall survival.
- Rapamycin treatment reduced p-mTOR and p-4E-BP1 but increased p-AKT in cancer cell lines.
Conclusions:
- p-mTOR and p-eIF-4E expression are associated with improved overall survival in ovarian cancer patients.
- These findings suggest that a specific patient subgroup may benefit from mTOR pathway inhibition.
- Future clinical trials should include biomarker testing to identify predictive markers for response to mTOR inhibitors.
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