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T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer.
Clin Cancer Res 2016; 22(24):6110-6117CC

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 IC50 values 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+Show Affiliations

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.Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.OncoTherapy Science Inc., Kawasaki, Kanagawa, Japan.OncoTherapy Science Inc., Kawasaki, Kanagawa, Japan.Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.Gynecologic Oncology Translational Research Unit, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan.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.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.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.Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. ynakamura@bsd.uchicago.edu koseih@saitama-med.ac.jp.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27334838

Citation

Ikeda, Yuji, et al. "T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 22, no. 24, 2016, pp. 6110-6117.
Ikeda Y, Park JH, Miyamoto T, et al. T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer. Clin Cancer Res. 2016;22(24):6110-6117.
Ikeda, Y., Park, J. H., Miyamoto, T., Takamatsu, N., Kato, T., Iwasa, A., ... Hasegawa, K. (2016). T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 22(24), pp. 6110-6117.
Ikeda Y, et al. T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer. Clin Cancer Res. 2016 Dec 15;22(24):6110-6117. PubMed PMID: 27334838.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer. AU - Ikeda,Yuji, AU - Park,Jae-Hyun, AU - Miyamoto,Takashi, AU - Takamatsu,Naofumi, AU - Kato,Taigo, AU - Iwasa,Akiko, AU - Okabe,Shuhei, AU - Imai,Yuichi, AU - Fujiwara,Keiichi, AU - Nakamura,Yusuke, AU - Hasegawa,Kosei, Y1 - 2016/06/22/ PY - 2016/01/26/received PY - 2016/05/27/revised PY - 2016/06/05/accepted PY - 2016/6/24/pubmed PY - 2018/1/13/medline PY - 2016/6/24/entrez SP - 6110 EP - 6117 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 22 IS - 24 N2 - 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 IC50 values 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. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/27334838/T_LAK_Cell_Originated_Protein_Kinase__TOPK__as_a_Prognostic_Factor_and_a_Potential_Therapeutic_Target_in_Ovarian_Cancer_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=27334838 DB - PRIME DP - Unbound Medicine ER -