title: T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer.
abstract: BACKGROUND
  We aimed to clarify the clinical significance of TOPK (T-lymphokine-activated killer cell-originated protein kinase) expression in ovarian cancer and evaluate the possible effect of TOPK inhibitors, OTS514 and OTS964, on ovarian cancer cells.
  
  
  METHODS
  TOPK expression was examined by immunohistochemistry using 163 samples with epithelial ovarian cancer (EOC). TOPK protein level and FOXM1 transcriptional level in ovarian cancer cell lines were examined by Western blot and RT-PCR, respectively. Half-maximum inhibitory concentration (IC50) values against TOPK inhibitors were examined by the MTT assay. Using the peritoneal dissemination model of ES-2 ovarian cancer cells, we examined the in vivo efficacy of OTS514. In addition, the cytotoxic effect of OTS514 and OTS964 on 31 patient-derived primary ovarian cancer cells was examined.
  
  
  RESULTS
  TOPK was expressed very highly in 84 (52%) of 163 EOC tissues, and high TOPK expression was significantly associated with poor progression-free survival and overall survival in early-stage cases of EOC (P = 0.008 and 0.006, respectively). Both OTS514 and OTS964 showed significant growth-inhibitory effect on ovarian cancer cell lines with IC50values of 3.0 to 46 nmol/L and 14 to 110 nmol/L, respectively. TOPK protein and transcriptional levels of FOXM1 were reduced by TOPK inhibitor treatment. Oral administration of OTS514 significantly elongated overall survival in the ES-2 abdominal dissemination xenograft model, compared with vehicle control (P < 0.001). Two drugs showed strong growth-inhibitory effect on primary ovarian cancer cells regardless of tumor sites or histological subtypes.
  
  
  CONCLUSIONS
  Our results demonstrated the clinical significance of high TOPK expression and potential of TOPK inhibitors to treat ovarian cancer. Clin Cancer Res; 22(24); 6110-7. ©2016 AACR.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.|Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: OncoTherapy Science Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: OncoTherapy Science Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Takamatsu
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Taigo
authors.initials: T
authors.lastname: Kato
authors.affiliation: Gynecologic Oncology Translational Research Unit, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwasa
authors.affiliation: OncoTherapy Science Inc., Kawasaki, Kanagawa, Japan.|Gynecologic Oncology Translational Research Unit, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Okabe
authors.affiliation: Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.|Gynecologic Oncology Translational Research Unit, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.|Gynecologic Oncology Translational Research Unit, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. ynakamura@bsd.uchicago.edu koseih@saitama-med.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan. ynakamura@bsd.uchicago.edu koseih@saitama-med.ac.jp.|Gynecologic Oncology Translational Research Unit, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015363:Quinolones / Q000627:therapeutic use; D013876:Thiophenes / Q000627:therapeutic use
chemical_list: D000072278:Forkhead Box Protein M1; C000617931:OTS514; C000622337:OTS964; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D013876:Thiophenes; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase