title: Targeting Cyclin-Dependent Kinases in Synovial Sarcoma: Palbociclib as a Potential Treatment for Synovial Sarcoma Patients.
abstract: In synovial sarcomas alterations in the cyclin D1-CDK4/6-Rb axis have been described. Also, β-catenin, a cyclin D1 regulator, is often overexpressed. Additionally, studies have shown that the t(X;18) translocation influences tumor behavior partly through cyclin D1 activation. We investigated how alterations in the cyclin D1-CDK4/6-Rb axis impact prognosis and studied effects of targeting this axis with the CDK4/6 inhibitor palbociclib.
  
  
  
  Synovial sarcoma samples (n = 43) were immunohistochemically stained for β-catenin, cyclin D1, p16, p21, p27, Rb, and phospho-Rb. Fluorescent in situ hybridization (FISH) was performed to detect CCND1 amplification or translocation. In 4 synovial sarcoma cell lines sensitivity to palbociclib was investigated using cell viability assays, and effects on the sensitive cell lines were evaluated on protein level and by cell cycle arrest.
  
  
  
  Expression of nuclear phospho-Rb and nuclear β-catenin in the patient samples was associated with poor survival. FISH showed a sporadic translocation of CCND1 in a subset of tumors. An 8-fold CCND1 amplification was found in 1 cell line, but not in the patient samples investigated. Palbociclib effectively inhibited Rb-phosphorylation in 3 cell lines, resulting in an induction of a G1 arrest and proliferation block.
  
  
  
  In this series nuclear phospho-Rb and nuclear β-catenin expression were negative prognostic factors. In vitro data suggest that palbociclib may be a potential treatment for a subset of synovial sarcoma patients. Whether this effect can be enhanced by combination treatment deserves further preclinical investigations.
authors.affiliation: Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. myrella.vlenterie@radboudumc.nl.
authors.forename: Myrella
authors.initials: M
authors.lastname: Vlenterie
authors.affiliation: Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Melissa H S
authors.initials: MH
authors.lastname: Hillebrandt-Roeffen
authors.affiliation: Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Esther W M
authors.initials: EW
authors.lastname: Schaars
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Uta E
authors.initials: UE
authors.lastname: Flucke
authors.affiliation: The Institute of Cancer Research London and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Emmy D G
authors.initials: ED
authors.lastname: Fleuren
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Navis
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: William P J
authors.initials: WP
authors.lastname: Leenders
authors.affiliation: Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Yvonne M H
authors.initials: YM
authors.lastname: Versleijen-Jonkers
authors.affiliation: Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.|The Institute of Cancer Research London and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013584:Sarcoma, Synovial / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010879:Piperazines; D011725:Pyridines; D016160:Retinoblastoma Protein; D051176:beta Catenin; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib