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Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative
T. Cuppens, D. Annibali, A. Coosemans, J. Trovik, N. Ter Haar, E. Colas, A. Garcia-Jimenez, K. Van de Vijver, RP. Kruitwagen, M. Brinkhuis, M. Zikan, P. Dundr, J. Huvila, O. Carpén, J. Haybaeck, F. Moinfar, HB. Salvesen, M. Stukan, C. Mestdagh,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
NLK
Free Medical Journals
od 1995 do Před 1 rokem
Freely Accessible Science Journals
od 1995
Open Access Digital Library
od 1995-01-01
Open Access Digital Library
od 1995-01-01
- MeSH
- cílená molekulární terapie MeSH
- fosfatidylinositol-3-kinasy genetika MeSH
- fosforylace MeSH
- inhibitory fosfoinositid-3-kinasy MeSH
- leiomyosarkom farmakoterapie genetika patologie MeSH
- lidé MeSH
- myši MeSH
- nádorové biomarkery genetika MeSH
- nádory dělohy farmakoterapie genetika patologie MeSH
- přežití bez známek nemoci MeSH
- prognóza MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- ribozomální protein S6 genetika MeSH
- signální transdukce účinky léků MeSH
- TOR serin-threoninkinasy antagonisté a inhibitory genetika MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design:We investigated the expression of several druggable targets (phospho-S6S240ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results:In uterine sarcomas and STUMPs, S6S240phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P= 0.001) and recurrence (P= 0.019), as shown by logistic regression. In addition, p-S6S240correlated with shorter progression-free survival (P= 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240in response prediction to PI3K/mTOR inhibition.Conclusions:Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240expression is a potential predictive biomarker for response to treatment.Clin Cancer Res; 23(5); 1274-85. ©2017 AACR.
Department of Development and Regeneration KU Leuven Leuven Belgium
Department of Gynecologic Oncology Oncology Center Provincial Hospitals Gdynia Gdynia Poland
Department of Gynecological Oncology UMC Utrecht Cancer Center Utrecht the Netherlands
Department of Obstetrics and Gynecology University of Bonn Bonn Germany
Department of Oncology Gynecologic Oncology KU Leuven Leuven Belgium
Department of Oncology Trace Platform KU Leuven UZ Leuven Leuven Belgium
Department of Pathology Hospital of the Sisters of Charity Linz Austria
Department of Pathology Leiden University Medical Center Leiden the Netherlands
Department of Pathology University of Turku and Turku University Hospital Turku Finland
Department of Pathology UZ Leuven KU Leuven Leuven Belgium
Department of Pathology Vall d'Hebron University Hospital Barcelona Spain
Institut de Pathologie et de Génétique Brussels Belgium
Institute of Pathology Medical University of Graz Graz Austria
Institute of Pathology University Hospital Cologne Cologne Germany
Laboratory for Pathology Oost Nederland Hengelo The Netherlands
Citace poskytuje Crossref.org
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