Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative

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...

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Published in:	Clinical cancer research Vol. 23; no. 5; pp. 1274 - 1285
Main Authors:	Cuppens, Tine, Annibali, Daniela, Coosemans, An, Trovik, Jone, Ter Haar, Natalja, Colas, Eva, Garcia-Jimenez, Angel, Van de Vijver, Koen, Kruitwagen, Roy P M, Brinkhuis, Mariël, Zikan, Michal, Dundr, Pavel, Huvila, Jutta, Carpén, Olli, Haybaeck, Johannes, Moinfar, Farid, Salvesen, Helga B, Stukan, Maciej, Mestdagh, Carole, Zweemer, Ronald P, Massuger, Leonardus F, Mallmann, Michael R, Wardelmann, Eva, Mints, Miriam, Verbist, Godelieve, Thomas, Debby, Gommé, Ellen, Hermans, Els, Moerman, Philippe, Bosse, Tjalling, Amant, Frédéric
Format:	Journal Article
Language:	English
Published:	United States American Association for Cancer Research Inc 01-03-2017
Subjects:	1-Phosphatidylinositol 3-kinase Animals Atrophy Biomarkers Biomarkers, Tumor - genetics Disease-Free Survival Endometrium Epidermal growth factor receptors ErbB-2 protein Experimental design Female Gene Expression Regulation, Neoplastic - drug effects Humans Inhibition Leiomyosarcoma - drug therapy Leiomyosarcoma - genetics Leiomyosarcoma - pathology Mathematical models Medicin och hälsovetenskap Mice Molecular Targeted Therapy Muscles Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - genetics Phosphorylation Predictions Prognosis PTEN protein Quality Regression analysis Ribosomal Protein S6 - genetics Sarcoma Shrinkage Signal Transduction - drug effects Smooth muscle Tissues TOR protein TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - genetics Tumors Uterine Neoplasms - drug therapy Uterine Neoplasms - genetics Uterine Neoplasms - pathology Uterus Xenograft Model Antitumor Assays Xenografts
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Summary:	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. We investigated the expression of several druggable targets (phospho-S6 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 , was tested in patient-derived xenograft (PDX) leiomyosarcoma models. In uterine sarcomas and STUMPs, S6 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade ( = 0.001) and recurrence ( = 0.019), as shown by logistic regression. In addition, p-S6 correlated with shorter progression-free survival ( = 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 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6 in response prediction to PI3K/mTOR inhibition. Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6 expression is a potential predictive biomarker for response to treatment. .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-0432 1557-3265 1557-3265
DOI:	10.1158/1078-0432.ccr-16-2149