title: Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative.
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-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.
authors.affiliation: Department of Oncology, Gynecologic Oncology, KU Leuven (University of Leuven), Leuven, Belgium.
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authors.affiliation: Department of Oncology, Gynecologic Oncology, KU Leuven (University of Leuven), Leuven, Belgium.
authors.forename: Daniela
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authors.lastname: Annibali
authors.affiliation: Department of Oncology, Laboratory of Tumor Immunology and Immunotherapy, ImmunOvar Research Group, KU Leuven (University of Leuven), Leuven, Belgium.|Department of Gynaecology and Obstetrics, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium.
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authors.lastname: Coosemans
authors.affiliation: Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.
authors.forename: Jone
authors.initials: J
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authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Natalja
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authors.lastname: Ter Haar
authors.affiliation: Biomedical Research Group in Gynecology, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Arnau de Vilanova University Hospital, University of Lleida, IRB Lleida, Lleida, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Colas
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Garcia-Jimenez
authors.affiliation: Department of Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, the Netherlands.
authors.forename: Koen
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authors.lastname: Van de Vijver
authors.affiliation: Department of Gynecology and Obstetrics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
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authors.initials: RP
authors.lastname: Kruitwagen
authors.affiliation: Laboratory for Pathology Oost Nederland, Hengelo, The Netherlands.
authors.forename: Mariël
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authors.lastname: Brinkhuis
authors.affiliation: Department of Obstetrics and Gynecology, Gynecological Oncology Center, Charles University in Prague - 1st Faculty of Medicine and General University Hospital in Prague, Czech Republic.
authors.forename: Michal
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authors.affiliation: Department of Pathology, Charles University in Prague - 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
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authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Jutta
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authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.|Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Johannes
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authors.affiliation: Department of Pathology, Hospital of the Sisters of Charity, Linz, Austria.
authors.forename: Farid
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authors.affiliation: Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.
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authors.initials: HB
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authors.affiliation: Department of Gynecologic Oncology, Oncology Center, Provincial Hospitals Gdynia, Gdynia, Poland.
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authors.affiliation: Institut de Pathologie et de Génétique, Brussels, Belgium.
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authors.affiliation: Department of Obstetrics and Gynecology, Radboud University Medical Centre Nijmegen, Nijmegen, the Netherlands.
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authors.initials: LF
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authors.affiliation: Department of Obstetrics and Gynecology, University of Bonn, Bonn, Germany.
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authors.initials: MR
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authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Eva
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authors.lastname: Wardelmann
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet at Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Miriam
authors.initials: M
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authors.affiliation: Department of Development and Regeneration, KU Leuven (University of Leuven), Leuven, Belgium.
authors.forename: Godelieve
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authors.affiliation: Department of Oncology, Trace Platform, KU Leuven (University of Leuven) - UZ Leuven, Leuven, Belgium.
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authors.affiliation: Department of Oncology, Trace Platform, KU Leuven (University of Leuven) - UZ Leuven, Leuven, Belgium.
authors.forename: Ellen
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authors.affiliation: Department of Oncology, Trace Platform, KU Leuven (University of Leuven) - UZ Leuven, Leuven, Belgium.
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authors.affiliation: Department of Pathology, UZ Leuven - KU Leuven (University of Leuven), Leuven, Belgium.
authors.forename: Philippe
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authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: Department of Oncology, Gynecologic Oncology, KU Leuven (University of Leuven), Leuven, Belgium. frederic.amant@uzleuven.be.|Centre for Gynecologic Oncology Amsterdam (CGOA), Antoni Van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, the Netherlands.
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mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011379:Prognosis; D038601:Ribosomal Protein S6 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D038601:Ribosomal Protein S6; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human