Development of molecular targeted therapy by the inhibition of MET-PAI-1 pathway for the prevention of thrombosis in cancer patients

• Project/Area Number: 26462509
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Tohoku University
• Principal Investigator: TOYOSHIMA Masafumi 東北大学, 大学病院, 講師 (70451581)
• Co-Investigator(Kenkyū-buntansha): 北谷 和之 東北大学, 東北メディカル・メガバンク機構, 助教 (40539235)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 卵巣明細胞腺癌 / 血栓症 / 遺伝子解析 / PAI-1 / ｃ-MET / 阻害剤 / c-MET / 卵巣明細胞腺がん / PAT-1

Outline of Final Research Achievements

For the purpose of preventing thrombosis in cancer patients, we investigated the effectiveness of MET-PAI-1 pathway inhibition in ovarian cancer. No significant differences were observed between several ovarian cancer tissue types by PAI-1 measurement in the blood by the ELISA method. In in vitro experiments, the addition of the PAI-1 inhibitor TM5275 inhibited the proliferation of ovarian cancer cell line ES-2 by G2 / M arrest. In addition, these phonotypes were confirmed in PAI-1 knockdown by siRNA. There was a significant difference in PAI-1 expression level between clear cell adenocarcinoma and serous adenocarcinoma by immunohistochemical staining of ovarian cancer patients’ sample. Furthermore, gene copy number analysis of ovarian clear cell adenocarcinoma was performed, and we found that the copy number of gene X, which is known to be involved in the coagulation system, was higher in DVT onset cases.

Research Products

• [Journal Article] Leptomeningeal metastasis from gynecologic cancers diagnosed by brain MRI (2017)
  • Author(s): Toyoshima M* (*corresponding author), Tsuji K, Shigeta S, Tokunaga H, Ito K, Watanabe Y, Yoshinaga K, Otsuki T, Niikura H, Yaegashi N
  • Journal Title: Clinical Imaging Volume: 41 Pages: 42-47
  • DOI: 10.1016/j.clinimag.2016.09.013
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ASGO 4th International Workshop on Gynecologic Oncology (2017)
  • Author(s): Shibuya Y, Toyoshima M* (*corresponding author), Yaegashi N
  • Journal Title: J Gynecol Onco Volume: 28（2） Issue: 1
  • DOI: 10.3802/jgo.2017.28.e24
  • Acknowledgement Compliant
• [Journal Article] Steroid Sulfatase Inhibitor Reduces Proliferation of Ishikawa Endometrial Cancer Cells in Co-Culture Systems (2016)
  • Author(s): Nishimoto M, Toyoshima M* (*corresponding author), Shiga N, Utsunomiya H,Tsuji K, Suzuki F, Nagase S, Suzuki T, Sasano H, Ito K, Yaegashi N
  • Journal Title: OJEMD Volume: 6 Issue: 09 Pages: 193-204
  • DOI: 10.4236/ojemd.2016.69025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cytokeratin 7-positive/cytokeratin 20-negative cecal adenocarcinoma metastatic to the uterine cervix: a case report (2016)
  • Author(s): Toyoshima M* (*corresponding author), Momono Y, Makino H, Kudo T, Oka N, Sakurada J, Suzuki H, Kodama H, Yoshinaga K
  • Journal Title: World Journal of Surgical Oncology Volume: - Issue: 1
  • DOI: 10.1186/s12957-016-0774-z
  • Peer Reviewed / Open Access
• [Journal Article] Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid (2015)
  • Author(s): Kitatani K, Usui T, Sriraman S, Toyoshima M, Ishibashi M, Shigeta S, Nagase S, Sakamoto M, Hannun Y, Torchilin V, Okazaki T, Ogiso H, Yaegashi N
  • Journal Title: Oncogene Volume: - Issue: 21 Pages: 2801-2812
  • DOI: 10.1038/onc.2015.330
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transferrin facilitates the formation of DNA double-strand breaks via transferrin receptor 1:the possible involvement of transferrin in carcinogenesis of high-grade serous ovarian cancer. (2015)
  • Author(s): Shigeta S, Toyoshima M* (*corresponding author), Ishibashi M, Usui T, Kitatani K*, Yaegashi N
  • Journal Title: Oncogene Volume: - Issue: 27 Pages: 3577-3586
  • DOI: 10.1038/onc.2015.425
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] 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
• [Presentation] 卵巣癌における c-Mycと合成致死作用を持つ 治療標的分子の探索 (2017)
  • Author(s): 湊 純子、豊島将文、北谷 和之、重田 昌吾、石橋 ますみ、八重樫 伸生
  • Organizer: 第5回婦人科がんバイオマーカー研究会学術集会
  • Place of Presentation: 大阪医科大学 本部北キャンパス（大阪府高槻市）
  • Year and Date: 2017-02-25
• [Presentation] 卵巣がんに対するセラミドナノリポソーム製剤の抗腫瘍作用 (2017)
  • Author(s): 張 雪薇、北谷和之、豊島将文、石橋ますみ、臼井利典、湊 純子、重田昌吾、Mark Kester、八重樫伸生
  • Organizer: 第5回婦人科がんバイオマーカー研究会学術集会
  • Place of Presentation: 大阪医科大学 本部北キャンパス（大阪府高槻市）
  • Year and Date: 2017-02-25
• [Presentation] 卵巣がん転移制御へのセラミド合成酵素 2 の関与 (2017)
  • Author(s): 北谷和之、張雪薇、臼井利典、豊島将文、重田昌吾、石橋ますみ、湊純子、小木曽英夫、岡崎俊朗、八重樫伸生
  • Organizer: 第5回婦人科がんバイオマーカー研究会学術集会
  • Place of Presentation: 大阪医科大学 本部北キャンパス（大阪府高槻市）
  • Year and Date: 2017-02-25
• [Presentation] フローサイトメトリーを利用した腹水細胞診断法のパイロットスタディ (2016)
  • Author(s): 徳永英樹、岡本聡、渡部洋、重田昌吾、辻圭太、海法道子、豊島将文、新倉仁、八重樫伸生
  • Organizer: 第55回日本臨床細胞学会秋期大会
  • Place of Presentation: 別府国際コンベンションセンターＢ-Ｃon Ｐlaza（大分県別府市）
  • Year and Date: 2016-11-18
• [Presentation] 子宮体癌のセンチネルリンパ節生検における捺印細胞診の診断精度についての検討 (2016)
  • Author(s): 佐藤いずみ、岡本聡、新倉仁、重田昌吾、橋本千明、辻圭太、徳永英樹、豊島将文、三浦弘守、渡部みか、八重樫伸生
  • Organizer: 第55回日本臨床細胞学会秋期大会
  • Place of Presentation: 別府国際コンベンションセンターＢ-Ｃon Ｐlaza（大分県別府市）
  • Year and Date: 2016-11-18
• [Presentation] セラミドナノリポソーム製剤によるネクロプト―シスの誘導 (2016)
  • Author(s): 張 雪薇、北谷 和之、豊島 将文、石橋 ますみ、臼井 利典、湊 純子、重田 昌吾、Mark Kester、八重樫 伸生
  • Organizer: 第9回セラミド研究会 学術集会
  • Place of Presentation: 東京ユビキタス協創広場CANVAS（東京都中央区）
  • Year and Date: 2016-10-27
• [Presentation] セラミドナノリポソームはネクロプトーシスを誘導する薬剤である (2016)
  • Author(s): 張雪薇、豊島将文、石橋ますみ、臼井利典、湊純子、重田昌吾、Ｍａｒｋ Ｋｅｓｔｅｒ，北谷和之、八重樫伸生
  • Organizer: 第89回日本生化学会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-27
• [Presentation] Involvement of the receptor tyrosine kinase TIE-1 in the platinum-resistance of ovarian cancer cells (2016)
  • Author(s): Ishibashi M, Toyoshima M, Zhang X, Minato J, Shigeta S, Kitatani K, Yaegashi N
  • Organizer: Marsha Rikin the 11th Ovarian Cancer Research Symposium
  • Place of Presentation: ワシントン大学（Seattle, USA）
  • Year and Date: 2016-09-12
  • Int'l Joint Research
• [Presentation] セラミドナノリポソームによる新しい細胞死ネクロプトーシス (2016)
  • Author(s): 張雪薇、北谷和之、石橋ますみ、湊純子、豊島将文、八重樫伸生
  • Organizer: 第15回日本婦人がん分子標的研究会
  • Place of Presentation: ホテルニューオータニ札幌（北海道札幌市）
  • Year and Date: 2016-08-20
• [Presentation] セラミド合成酵素による癌転移制御 (2016)
  • Author(s): 北谷和之，張雪薇，臼井利典，豊島将文，重田昌吾，Mahy Egiz，湊 純子，石橋ますみ，小木曽英夫， 岡崎俊朗，八重樫伸生
  • Organizer: 第58回日本脂質生化学会
  • Place of Presentation: 秋田キャッスルホテル（秋田市）
  • Year and Date: 2016-06-10
• [Presentation] 卵巣がん細胞に対するセラミド卵巣がん細胞に対するセラミドナノリポソームの抗腫瘍効果-ネクロプト－シスの誘導- (2016)
  • Author(s): 張 雪薇, 豊島 将文, 石橋 ますみ, 臼井 利典, 湊 純子, 重田 昌吾, Mark Kester, 北谷 和之, 八重樫伸生
  • Organizer: 第58回日本脂質生化学会
  • Place of Presentation: 秋田キャッスルホテル（秋田市）
  • Year and Date: 2016-06-09
• [Presentation] 子宮頸癌のセンチネルリンパ節生検における捺印細胞診の診断精度についての検討 (2016)
  • Author(s): 佐藤いずみ、岡本聡、新倉仁、橋本千明、徳永英樹、豊島将文、三浦弘守、渡部みか、渡部洋、八重樫伸生
  • Organizer: 第57回日本臨床細胞学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-05-29
• [Presentation] Casein kinase I epsilon is a novel molecular target for c-Myc driven ovarian cancers (2016)
  • Author(s): Toyoshima M, Kitatani K, Shigeta S, Ishibashi M, Hasegawa-Minato J, Yaegashi N
  • Organizer: 第68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: 2016-04-22
• [Presentation] Transferrin is involved in the carcinogenesis of high-grade serous ovarian cancer by facilitating the DNA double-strand breaks via transferrin receptor 1 in fallopian tube. (2016)
  • Author(s): Shigeta Ｓ, Toyoshima M, Kitatani K, Ishibashi M, Minato J, Yaegashi N
  • Organizer: 第68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: 2016-04-22
• [Presentation] Furin, a pro-protein convertase, is a novel molecular target for c-Myc-driven ovarian cancers (2016)
  • Author(s): Minato J, Toyoshima M, Kitatani K, Shigeta S, Ishibashi M, Yaegashi N
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 京都国際会館（京都市）
  • Year and Date: 2016-04-05
  • Int'l Joint Research
• [Presentation] Transferrin in follicular fluid can facilitate DNA double-strand breaks to fallopian tube epithelium: possible involvement of transferrin in the carcinogenesis of high-grade serous ovarian cancer. (2016)
  • Author(s): Shogo Shigeta, Masafumi Toyoshima, Kazuyuki Kitatani, Masumi Ishibashi, Toshinori Usui, Junko Minato, Nobuo Yaegashi
  • Organizer: Society for Reproductive Investigation 63th scientific annual meeting
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2016-03-16
  • Int'l Joint Research
• [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 (2016)
  • Author(s): 石橋 ますみ、豊島 将文、Mahy Egiz、張 雪薇、湊 純子、重田 昌吾、北谷 和之、八重樫 伸生
  • Organizer: 第4回婦人科がんバイオマーカー研究会学術集会
  • Place of Presentation: 岐阜大学サテライトキャンパス（岐阜市）
  • Year and Date: 2016-02-27
• [Presentation] 卵巣がん転移に関わるセラミド生成代謝酵素 (2016)
  • Author(s): 北谷和之，張雪薇，臼井利典，豊島将文，重田昌吾，石橋ますみ，湊純子， 小木曽英夫， 岡崎俊朗，八重樫伸生
  • Organizer: 第4回婦人科がんバイオマーカー研究会学術集会
  • Place of Presentation: 岐阜大学サテライトキャンパス（岐阜市）
  • Year and Date: 2016-02-27
• [Presentation] Transferrin facilitates the formation of DNA-double strand breaks via Transferrin receptor 1 in fallopian tube epithelial cells. (2015)
  • Author(s): Shogo Shigeta, Masafumi Toyoshima, Kazuyuki Kitatani, Junko Minato, Masumi Ishibashi, Toshinori Usui, Nobuo Yaegashi
  • Organizer: AACR special conference Advance in Ovarian Cancer Research
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] 卵巣癌におけるc-mycと合成致死作用を持つ治療標的分子の探索 (2015)
  • Author(s): 湊純子、豊島将文、北谷和之、重田昌吾、石橋ますみ、臼井利典、八重樫伸生
  • Organizer: 第14回日本婦人科がん分子標的研究会
  • Place of Presentation: 美ヶ原温泉ホテル翔峰（長野県松本市）
  • Year and Date: 2015-07-18
• [Presentation] 月経血や卵胞液に含まれるトランスフェリンはⅠ型トランスフェリン受容体を介して卵管上皮細胞におけるDNA二重鎖切断を誘導・増幅する (2015)
  • Author(s): 重田昌吾・豊島将文・北谷和之・石橋ますみ・八重樫伸生
  • Organizer: 第67回日本産科婦人科学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-10
• [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