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SHR Neuro Cancer Cardio Lipid Metab Microb

Cuppens, T; Annibali, D; Coosemans, A; Trovik, J; Ter Haar, N; Colas, E; Garcia-Jimenez, A; Van de Vijver, K; Kruitwagen, RP; Brinkhuis, M; Zikan, M; Dundr, P; Huvila, J; Carpén, O; Haybaeck, J; Moinfar, F; Salvesen, HB; Stukan, M; Mestdagh, C; Zweemer, RP; Massuger, LF; Mallmann, MR; Wardelmann, E; Mints, M; Verbist, G; Thomas, D; Gommé, E; Hermans, E; Moerman, P; Bosse, T; Amant, F.
Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative.
Clin Cancer Res. 2017; 23(5):1274-1285 Doi: 10.1158/1078-0432.CCR-16-2149 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

Co-authors Med Uni Graz: Haybäck Johannes; Moinfar Farid
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Abstract:: 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-S6^S240 ribosomal 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-S6^S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6^S240 phosphorylation (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-S6^S240 correlated 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-S6^S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6^S240 in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6^S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274-85. ©2017 AACR. ©2017 American Association for Cancer Research.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Biomarkers, Tumor - genetics; Disease-Free Survival -; Female -; Gene Expression Regulation, Neoplastic - drug effects; Humans -; Leiomyosarcoma - drug therapy; Leiomyosarcoma - genetics; Leiomyosarcoma - pathology; Mice -; Molecular Targeted Therapy -; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - genetics; Phosphorylation -; Prognosis -; Ribosomal Protein S6 - genetics; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; Uterine Neoplasms - drug therapy; Uterine Neoplasms - genetics; Uterine Neoplasms - pathology; Xenograft Model Antitumor Assays -