1. Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative
- Author
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Mariël Brinkhuis, Miriam Mints, Tjalling Bosse, Koen Van de Vijver, Debby Thomas, R.P.F.M. Kruitwagen, Ronald P. Zweemer, Helga B. Salvesen, Michal Zikan, Tine Cuppens, Carole Mestdagh, Jone Trovik, Ellen Gomme, Pavel Dundr, Philippe Moerman, Godelieve Verbist, Jutta Huvila, Michael R. Mallmann, Maciej Stukan, Natalja T. ter Haar, Farid Moinfar, Els Hermans, Daniela Annibali, Johannes Haybaeck, Angel Garcia-Jimenez, Frédéric Amant, Olli Carpén, An Coosemans, Eva Wardelmann, Eva Colas, Leonardus F. Massuger, Amsterdam Reproduction & Development (AR&D), Other departments, Medicum, Department of Pathology, Precision Cancer Pathology, MUMC+: MA Arts Assistenten Obstetrie Gynaecologie (9), MUMC+: MA Medische Staf Obstetrie Gynaecologie (9), RS: GROW - R2 - Basic and Translational Cancer Biology, and Obstetrie & Gynaecologie
- Subjects
0301 basic medicine ,Leiomyosarcoma ,Cancer Research ,Pathology ,AKT-MTOR PATHWAY ,ENDOMETRIAL STROMAL SARCOMA ,Uterine sarcoma ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Molecular Targeted Therapy ,Phosphorylation ,CYCLIN D1 ,Phosphoinositide-3 Kinase Inhibitors ,Ribosomal Protein S6 ,Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] ,biology ,Soft tissue sarcoma ,TOR Serine-Threonine Kinases ,Prognosis ,Immunohistochemistry ,TUMORS ,Gene Expression Regulation, Neoplastic ,PI3K/mTOR pathway ,SOFT-TISSUE SARCOMA ,Oncology ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,TRIAL ,Female ,Signal Transduction ,EXPRESSION ,medicine.medical_specialty ,Stromal cell ,3122 Cancers ,Disease-Free Survival ,03 medical and health sciences ,medicine ,Biomarkers, Tumor ,PTEN ,BREAST-CANCER ,Animals ,Humans ,PI3K/AKT/mTOR pathway ,Endometrial stromal sarcoma ,business.industry ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,MAMMALIAN TARGET ,Patient-derived xenograft models ,Cancer research ,biology.protein ,business ,GROWTH-FACTOR RECEPTOR - 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-S6S240 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-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models. Results: In uterine sarcomas and STUMPs, S6S240 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-S6S240 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-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition. Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274–85. ©2017 AACR.
- Published
- 2017