title: Inhibition of MAPK and VEGFR by Sorafenib Controls the Progression of Endometriosis.
abstract: BACKGROUND
  Sorafenib is a strong multikinase inhibitor targeting 2 different pathways of endometriosis pathogenesis: RAF kinase and vascular endothelial growth factor receptor (VEGFR). We investigate whether Sorafenib could control the growth of endometriotic lesions both in vitro and in vivo.
  
  
  METHODS
  Stromal primary cells were extracted from endometrial and endometriotic biopsies from patients with (n = 10) and without (n = 10) endometriosis. Proliferation, apoptosis, mitogen-activated protein kinases, and VEGFR-2 autophosphorylation were explored with and without Sorafenib treatment. Human endometriotic lesions were implanted in 30 nude mice randomized according to Sorafenib or placebo treatment.
  
  
  RESULTS
  Treating endometriotic cells with Sorafenib abrogated the phosphorylation of extracellular signal-regulated kinase in stromal cells of women with endometriosis compared to controls. In addition, this study highlights the antiangiogenic role of Sorafenib which translates as a decreased phosphorylated VEGFR-2-VEGFR-2 ratio in endometriosis. Using a xenogenic mouse model of endometriosis, we confirmed that Sorafenib regulates the endometriosis activity in vivo by targeting endometriosis-related proliferation and inflammation.
  
  
  CONCLUSIONS
  Our data suggest that Sorafenib controls the growth of endometriotic lesions in vitro and in vivo.
authors.affiliation: Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France Department of Digestive and Endocrine Surgery, Hôpital Cochin, AP-HP, Paris cedex, France.
authors.forename: Mahaut
authors.initials: M
authors.lastname: Leconte
authors.affiliation: Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France Department of Gynecology Obstetrics II and Reproductive Medicine, Faculty of Medicine, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, Centre Hospitalier Universitaire Cochin, University Paris Descartes, Sorbonne Paris Cité, Paris, France Institut Cochin, University Paris Descartes, Sorbonne Paris Cité CNRS (UMR 8104), Paris, France pietro.santulli@cch.aphp.fr.
authors.forename: Pietro
authors.initials: P
authors.lastname: Santulli
authors.affiliation: Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chouzenoux
authors.affiliation: Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France Department of Gynecology Obstetrics II and Reproductive Medicine, Faculty of Medicine, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, Centre Hospitalier Universitaire Cochin, University Paris Descartes, Sorbonne Paris Cité, Paris, France Institut Cochin, University Paris Descartes, Sorbonne Paris Cité CNRS (UMR 8104), Paris, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Marcellin
authors.affiliation: Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cerles
authors.affiliation: Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France Department of Gynecology Obstetrics II and Reproductive Medicine, Faculty of Medicine, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, Centre Hospitalier Universitaire Cochin, University Paris Descartes, Sorbonne Paris Cité, Paris, France Institut Cochin, University Paris Descartes, Sorbonne Paris Cité CNRS (UMR 8104), Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Chapron
authors.affiliation: Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France Department of Digestive and Endocrine Surgery, Hôpital Cochin, AP-HP, Paris cedex, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dousset
authors.affiliation: Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France Department of Immunology, Hôpital Cochin, AP-HP, Paris cedex, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004715:Endometriosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004717:Endometrium / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000637:transplantation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D017154:Stromal Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000637:transplantation; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: MAPK; RAF kinase; VEGFR-2; endometriosis; sorafenib