The therapeutic strategy toward overcoming drug resistance of gynecologic cancers utilizing high throughput screening.

• Project/Area Number: 24390375
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Tohoku University
• Principal Investigator: YAEGASHI Nobuo 東北大学, 医学(系)研究科(研究院), 教授 (00241597)
• Co-Investigator(Kenkyū-buntansha): TOYOSHIMA Masafumi 東北大学, 大学院医学系研究科, 非常勤講師 (70451581)
• Co-Investigator(Renkei-kenkyūsha): NAGASE Satoru 山形大学, 医学部, 教授 (00292326) ; SUZUKI Fumihiko 東北大学, 大学院医学系研究科, 助教 (20400343)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2012: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: スクリーニング / 薬剤耐性 / 婦人科がん / 化学療法 / シスプラチン

Outline of Final Research Achievements

The purpose of this study is to search the molecules that can cancel the cisplatin resistance of cancer cells. We explore the molecules that show a synthetic lethal effect with a small amount of CDDP administration in a high-throughput screening using siRNA library consisting of 6650 genes. As a result, a strong expression of TIE-1 was found to be decrease the sensitivity toward cisplatin in several ovarian cancer cell lines. The relationship among TIE-1, ovarian cancer and/or drug resistance has not been reported. In order to examine the significance of TIE-1 expression in ovarian cancer patients, in silico analysis was carried out. We confirmed that TIE-1 high expression group has a significantly poor prognosis by examination of the overall survival in 1582 ovarian cancer patients. Furthermore, we confirmed that apoptosis and γH2AX expressions, a marker for DNA-double strand breaks, were significantly decreased during CDDP administration in TIE-1 over-expressed cells.

Research Products

• [Journal Article] Inhibition of plasminogen activator inhibitor-1 is a potential therapeutic strategy in ovarian cancer. (2015)
  • Author(s): Mashiko S, Kitatani K, Toyoshima M, Ichimura A, Dan T, Usui T, Ishibashi M, Shigeta S, Nagase S, Miyata T, Yaegashi N
  • Journal Title: Cancer Biology & Therapy Volume: 16 Issue: 2 Pages: 253-260
  • DOI: 10.1080/15384047.2014.1001271
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Solitary uterine metastasis of invasive lobular carcinoma after adjuvant endocrine therapy: a case report. (2015)
  • Author(s): Toyoshima M, Iwahashi H, Shima T, Hayasaka A, Kudo T, Makino H, Igeta S, Matsuura R, Ishigaki N, Akagi K, Sakurada J, Suzuki H, Yoshinaga K
  • Journal Title: Journal of Medical Case Reports Volume: 9 Issue: 1 Pages: 47-47
  • DOI: 10.1186/s13256-014-0511-6
  • Peer Reviewed / Open Access
• [Journal Article] Spontaneous retroperitoneal hemorrhage caused by rupture of an ovarian artery aneurysm: a case report and review of the literature. (2015)
  • Author(s): Toyoshima M, Kudo T, Igeta S, Makino H, Momono Y, Shima T, Matsuura R, Ishigaki N, Akagi K,Takeyama Y, Iwahashi H, Rikimaru H, Sato A, Yoshinaga K
  • Journal Title: Journal of Medical Case Reports Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Clinical outcome of pelvic exenteration in patients with advanced or recurrent uterine cervical cancer. (2014)
  • Author(s): Tanaka S, Nagase S, Kaiho-Sakuma M, Nagai T, Kurosawa H, Toyoshima M, Tokunaga H, Otsuki T, Utsunomiya H, Takano T, Niikura H, Ito K, Yaegashi N.
  • Journal Title: Int J Clin Oncol Volume: 19 Issue: 1 Pages: 133-138
  • DOI: 10.1007/s10147-013-0534-9
  • Peer Reviewed
• [Journal Article] Paclitaxel-carboplatin for advanced or recurrent carcinosarcoma of the uterus: the Japan Uterine Sarcoma Group and Tohoku Gynecologic Cancer Unit Study (2014)
  • Author(s): Tadao Takano,Takeo Otsuki,Hideki Tokunaga,Masafumi Toyoshima,Hiroki Utsunomiya,Satoru Nagase,Hitoshi Niikura,Kiyoshi Ito,Nobuo Yaegashi,Hidekazu Yamada,Toru Tase,Masahiro Kagabu,Tadahiro Shoji,Toru Sugiyama,Naoki Sato,Toshio Fujimoto,Yukihiro Terada, Junzo Kigawa,et al
  • Journal Title: Int J Clin Oncol. Volume: accepted Issue: 6 Pages: 1052-1058
  • DOI: 10.1007/s10147-013-0658-y
  • Peer Reviewed
• [Journal Article] Molecular Pathogenesis of Uterine Serous Carcinoma (2014)
  • Author(s): Satoru Nagase ・ Fumihiko Suzuki ・ Hideki Tokunaga ・Masafumi Toyoshima ・ Hiroki Utsunomiya ・Hitoshi Niikura ・ Nobuo Yaegashi
  • Journal Title: Curr Obstet Gynecol Rep Volume: 3 Issue: 1 Pages: 33-39
  • DOI: 10.1007/s13669-013-0069-0
  • Peer Reviewed
• [Journal Article] Evaluation of Postoperative Chemotherapy in Patients with Uterine Carcinosarcoma: A Retrospective Survey of the Tohoku Gynecologic Cancer Unit. (2014)
  • Author(s): Otsuki A, Otsuki T, Tokunaga H, Niikura H, Nagase S, Sugiyama T, Toyoshima M, Utsunomiya H, Yokoyama Y, Mizunuma H, Sato N, Terada Y, Shoji T, Sugiyama T, Nakahara K, Ohta T, Yamada H, Tase T, Nishiyama H, Fujimori K, Takano T, Takahashi F, Watanabe Y, Yaegashi N
  • Journal Title: International Journal of Clinical Oncology Volume: in press
  • Peer Reviewed
• [Journal Article] Outcomes of Abdominal Radical Trachelectomy: Results of a Multicenter Prospective Cohort Study in a Tohoku Gynecologic Cancer Unit. (2014)
  • Author(s): Tokunaga H, Watanabe Y, Niikura H, Nagase S, Toyoshima M, Shiro R, Yoshihito Yokoyama Y, Mizunuma H, Ohta T, Nishiyama H, Watanabe T, Sato N, Sugiyama T, Takano T, Takahashi F, Yaegashi N
  • Journal Title: International Journal of Clinical Oncology Volume: in press Issue: 4 Pages: 776-780
  • DOI: 10.1007/s10147-014-0763-6
  • Peer Reviewed
• [Journal Article] Feasibility study of gemcitabine plus docetaxel in advanced or recurrent uterine leiomyosarcoma and undifferentiated endometrial sarcoma in Japan (2013)
  • Author(s): Takano T, Niikura H, Ito K, Nagase S, Utsunomiya H, Otsuki T, Toyoshima M, Tokunaga H, Kaiho-Sakuma M, Shiga N, Nagai T, Tanaka S, Otsuki A, Kurosawa H, Shigeta S, Yamaguchi T, Yaegashi N.
  • Journal Title: International Journal of Clinical Oncology. Volume: - Issue: 5 Pages: 897-905
  • DOI: 10.1007/s10147-013-0627-5
  • Peer Reviewed
• [Journal Article] Small Cell Carcinoma of the Uterine Cervix: Clinical Outcome of Concurrent Chemoradiotherapy with a Multidrug Regimen (2013)
  • Author(s): Hideki Tokunaga, Satoru Nagase, Kosuke Yoshinaga, Sota Tanaka, Tomyuki Nagai, Hiroki Kurosawa, Michiko Kaiho-Sakuma, Masafumi Toyoshima, et al
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 229 Issue: 1 Pages: 75-81
  • DOI: 10.1620/tjem.229.75
  • NAID: 130004460037
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed
• [Journal Article] Functional Genomics Identifies Therapeutic Targets for MYC-Driven Cancer (2012)
  • Author(s): Masafumi Toyoshima , Heather L Howie , Maki Imakura , Ryan M Walsh , James E Annis , Aaron N. Chang ,et al
  • Journal Title: PNAS Volume: 109 Issue: 24 Pages: 9545-9550
  • DOI: 10.1073/pnas.1121119109
  • Peer Reviewed
• [Journal Article] Hysterescopic inspection and total curettage are insufficient fordiscriminating endometrial cancer from atypical endometrial hyperplasia (2012)
  • Author(s): Hiroki Kurosawa, Kiyoshi ito, Hitoshi Nikura, Tadao Takano, Satoru Nagase, Hiroki Ustunomiya, Takeo Otsuki, Masafumi Toyoshima, Tomoyuki Nagai, Souta Tanaka, Mika Watanabe and Nobuo Yaegashi
  • Journal Title: Tohoku J. Exp. Med. Volume: 228 Pages: 365-370
  • Peer Reviewed
• [Presentation] Transferrin facilitates DNA-double strand breaks via transferrin receptor 1 in human fallopian tube epithelial cells: possible involvement of transferrin in carcinogenesis. (2015)
  • Author(s): Shigeta S, Toyoshima M, Kitatani K, Ishibashi M, Usui T, Yaegashi N
  • Organizer: Society for Reproductive Investigation 62th scientific annual meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-03-27
• [Presentation] セラミドによる卵巣がん播種転移制御 (2015)
  • Author(s): 北谷和之、豊島将文、臼井利典、重田昌吾、石橋ますみ、永瀬智、八重樫伸生
  • Organizer: 第3回婦人科がんバイオマーカー研究会学術集会
  • Place of Presentation: 九州大学医学部百年講堂（福岡市）
  • Year and Date: 2015-02-21
  • Invited
• [Presentation] スフィンゴ脂質セラミドを利用した卵巣がん播種転移薬の可能性 (2014)
  • Author(s): 北谷和之、豊島将文、臼井利典、重田昌吾、石橋ますみ、永瀬智、八重樫伸生
  • Organizer: 第2回婦人科がんバイオマーカー研究会学術集会
  • Place of Presentation: 東京慈恵会医科大学（東京都港区）
  • Year and Date: 2014-07-04
• [Presentation] Investigation of PAI-1 as a new therapeutic target for ovarian cancer. (2014)
  • Author(s): Satsuki Mashiko, Masafumi Toyoshima, Kazuyuki Kitatani , Shogo Shigeta , Masumi Ishibashi , Nobuo Yaegashi
  • Organizer: 第66回日本産科婦人科学会学術総会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2014-04-19
• [Presentation] セラミドによる細胞運動性の調節：セラミドリポソームの抗卵巣がん播種転移薬としての可能性 (2014)
  • Author(s): 北谷和之，豊島将文，増子さつき，重田昌吾，石橋ますみ，永瀬智，八重樫伸生
  • Organizer: 第66回日本産科婦人科学会学術総会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2014-04-18
• [Presentation] 大規模 siRNA スクリーニングを用いた 卵巣がんのシスプラチン抵抗性を克服する分子標的の検討 (2014)
  • Author(s): 石橋ますみ、豊島将文、北谷和之、増子さつき、重田昌吾、八重樫伸生
  • Organizer: 第66回日本産科婦人科学会学術総会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2014-04-18
• [Presentation] 大規模siRNAスクリーニングを用いた卵巣がんのシスプラチン抵抗性を克服する分子標的の検討 (2013)
  • Author(s): 石橋ますみ、豊島将文、北谷和之、増子さつき、重田昌吾、八重樫伸生
  • Organizer: 第1回婦人科がんバイオマーカー研究会学術集会
  • Place of Presentation: 東京大学 伊藤国際学術研究センター
  • Year and Date: 2013-02-16
• [Presentation] c-Myc高発現をバイオマーカーとした卵巣がんにおける治療標的分子の同定 (2013)
  • Author(s): 豊島将文、北谷和之、増子さつき、重出昌吾、石橋ますみ、八重樫伸生
  • Organizer: 第1回婦人科がんバイオマーカー研究会学術集会
  • Place of Presentation: 東京大学 伊藤国際学術研究センター
  • Year and Date: 2013-02-16
• [Presentation] Identification of Targeted therapies for Ovarian Cancer by Functional Genomics (2012)
  • Author(s): Masafumi Toyoshima
  • Organizer: Marsha Rikin the 9th Ovarian Cancer Research Symposium
  • Place of Presentation: Seattle, USA(招待講演)
  • Year and Date: 2012-09-07
• [Presentation] 卵巣がん転移を標的にした創薬:スフィンゴ脂質の利用
  • Author(s): 北谷和之・豊島将文・増子さつき・重田昌吾・石橋ますみ・八重樫伸生
  • Organizer: 第12回日本婦人科がん分子標的研究会
  • Place of Presentation: 東大寺総合文化センター、奈良市
• [Presentation] 卵巣明細胞腺癌におけるPAI-1の発現と血栓症発症の関連についての検討
  • Author(s): 増子さつき・豊島将文・北谷和之・重田昌吾・八重樫伸生
  • Organizer: 第65回日本産科婦人科学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] 卵管上皮内腺癌におけるDNA二本鎖切断とp53発現の免疫組織学的検討
  • Author(s): 重田昌吾・豊島将文・増子さつき・北谷和之・八重樫伸生
  • Organizer: 第65回日本産科婦人科学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] Identification of Targeted Therapies for Ovarian Cancers by Functional Genomics
  • Author(s): Masafumi Toyoshima, Kazuyuki Kitatani, Satsuki Mashiko, Shogo Shigeta and Nobuo Yaegashi
  • Organizer: 第65回日本産科婦人科学会学術総会
  • Place of Presentation: 札幌市