Utilization of genomic signatures to identify high efficacy candidate drugs for chemo-refractory endometrial cancers.

• Project/Area Number: 23791836
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Kyoto University
• Principal Investigator: BABA Tsukasa 京都大学, 医学研究科, 講師 (60508240)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 婦人科腫瘍学 / 子宮体癌 / マイクロアレイ / 抗癌剤耐性 / 漿液性腺癌

Research Abstract

Endometrial cancer, one of the most common gynecologic malignancies, is increasing in Japan, nearly doubling over the last decade. High grade disease patients are often resistant to conventional chemotherapy with platinum agents; therefore discovery of efficacious new drugs in this setting is required to benefit chemo-refractory cases. Through bioinformatic analysis using the NCI60 panel of cell lines with in vivo endometrial cancer data (GSE2109) and in vitro data (GSE25458), we at first calculated susceptibility scores to identify candidate drugs for chemo-refractory cases. Fludarabine and Temsirolimus showed higher susceptibility scores in high grade cases compared with cisplatin, doxorubicin, and paclitaxel. Fludarabine significantly inhibited cell proliferation and increased apoptosis in the cisplatin-resistant endometrial cancer cell line, HEC1A, relative to HEC50B (p<0.001). Fludarabine treatment also enhanced Caspase 3/7 activity in HEC1A relative to HEC50B cells (p<0.001), and inhibited the growth of HEC1A xenograft tumors relative to cisplatin (p<0.05). Conclusions: These results support that identification and use of genomic signatures can lead to identification of n ew therapeutic candidates that may prove beneficial to chemo -resistant cases. Fludarabine may be useful in targeting high grade, chemo-refractory endometrial cancer.

Research Products

• [Journal Article] Utilization of genomic signatures to identify high efficacy candidate drugs for chemo-refractory endometrial cancers. (2013)
  • Author(s): Kharma B, Baba T, Mandai M, Matsumura N, Murphy SK, Kang HS, Yamanoi K, Hamanishi J, Yamaguchi K, Yoshioka Y, Konishi I.
  • Journal Title: Int J Cancer. Volume: 133 Issue: 9 Pages: 2234-44
  • DOI: 10.1002/ijc.28220
  • Peer Reviewed
• [Journal Article] Eph-ephrin A system regulates human choriocarcinoma-derived JEG-3 cell invasion. (2013)
  • Author(s): Fujiwara H, Nishioka Y, Matsumoto, H Suginami K, Horie A, Tani H, Matsumura N, Baba T, Sato Y, Araki Y, Konishi I
  • Journal Title: Int J Gynecol Cancer. Volume: 23 Issue: 3 Pages: 576-582
  • DOI: 10.1097/igc.0b013e3182849e36
  • Peer Reviewed
• [Journal Article] Clinical Management of Atypical Polypoid Adenomyoma of the Uterus. A Clinicopathological Review of 29 Cases (2013)
  • Author(s): Matsumoto T, Hiura M, Baba T, Ishiko O, Shiozawa T, Yaegashi N, Kobayashi H, Yoshikawa H, Kawamura N, Kaku T
  • Journal Title: Gynecol Oncol Volume: 129(1) Issue: 1 Pages: 54-57
  • DOI: 10.1016/j.ygyno.2012.12.040
  • Peer Reviewed
• [Journal Article] PD-L1 on Tumor Cells Is Induced in Ascites and Promotes Peritoneal Dissemination of Ovarian Cancer through CTL Dysfunction. (2013)
  • Author(s): Abiko K, Mandai M, Hamanishi J, Yoshioka Y, Matsumura N, Baba T, Yamaguchi K, Murakami R, Yamamoto A, Kharma B, Kosaka K, Konishi I.
  • Journal Title: Clin Cancer Res. Volume: 19 Issue: 6 Pages: 1363-1374
  • DOI: 10.1158/1078-0432.ccr-12-2199
  • Peer Reviewed
• [Journal Article] Utilization of genomic signatures to identify high efficacy candidate drugs for chemo-refractory endometrial cancers (2013)
  • Author(s): Kharma B, Baba T, Konishi I, et al
  • Journal Title: Int J Cancer Volume: 132
  • Peer Reviewed
• [Journal Article] Expression of p53 and p21(WAF-1), apoptosis, and proliferation of smooth muscle cells in normal myometrium during the menstrual cycle: implication of DNA damage and repair for leiomyoma development. (2012)
  • Author(s): Suzuki A, Kariya M, Matsumura N, Baba T, Yagi H, Mandai M, Konishi I, Fujii S.
  • Journal Title: Med Mol Morphol. Volume: 45(4) Issue: 4 Pages: 214-21
  • DOI: 10.1007/s00795-011-0562-3
  • Peer Reviewed
• [Journal Article] Adenoid cystic carcinoma of skene glands: a rare origin in the female genital tract and the characteristic clinical course. (2012)
  • Author(s): Ueda Y, Mandai M, Matsumura N, Baba T, Suzuki A, Yoshioka Y, Kosaka K, Konishi I.
  • Journal Title: Int J Gynecol Pathol. Volume: 31(6) Issue: 6 Pages: 596-600
  • DOI: 10.1097/pgp.0b013e31824d357e
  • Peer Reviewed
• [Journal Article] Synchronous primary corpus and ovarian cancer: High incidence of endometriosis and thrombosis (2012)
  • Author(s): Yamanoi K, Mandai M, Suzuki A, Matsumura N, Baba T, Yoshioka K, Kosaka K, Konishi I
  • Journal Title: Oncol Lett Volume: 4(3) Issue: 3 Pages: 375-380
  • DOI: 10.3892/ol.2012.770
  • Peer Reviewed
• [Journal Article] Phase II study of oral et oposide and intravenous irinotecan for patients with platinum-resistant and taxane-pretreated ovarian cancer : Japan Clinical Oncology Group Study 0503 (2012)
  • Author(s): Matsumoto K, Katsumata N, Saito I, Shibata T, Konishi I, Fukuda H, Kamura T.
  • Journal Title: Jpn J Clin Oncol Volume: 42(3) Issue: 3 Pages: 222-5
  • DOI: 10.1111/j.1447-0756.2011.01752.x
  • Peer Reviewed
• [Journal Article] Solitary fibrous tumor arising slowly in the vulva over 10 years : Case report and review (2012)
  • Author(s): Taki M, Baba T, Mandai M, Suzuki A, Mikami Y, Matsumura N, Konishi I.
  • Journal Title: J Obstet Gynaecol Res Volume: 38(5) Issue: 5 Pages: 884-8
  • DOI: 10.1111/j.1447-0756.2011.01792.x
  • Peer Reviewed
• [Journal Article] Synchronous primary corpus and ovarian cancer: High incidence of endometriosis and thrombosis. (2012)
  • Author(s): Yamanoi K, Baba T, Konishi I, et al
  • Journal Title: Oncol Lett Volume: 4 Pages: 375-80
  • Peer Reviewed
• [Journal Article] The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer (2012)
  • Author(s): Yamamura S, Matsumura N, Mandai M, Huang Z, Oura T, Baba T, Hamanishi J, Yamaguchi K, Kang HS, Okamoto T, Abiko K, Mori S, Murphy SK, Konishi I
  • Journal Title: Int J Cancer Volume: 130(1) Pages: 20-8
  • Peer Reviewed
• [Journal Article] Primary squamous cell carcinoma of fallopian tube accompanied by gastric metaplasia of female genital tract : case report and review (2011)
  • Author(s): Satoh H, Baba T, Mandai M, Suzuki A, Matsumura N, Konishi I.
  • Journal Title: J Obstet Gynaecol Res Volume: 37(8) Issue: 8 Pages: 1106-11
  • DOI: 10.1111/j.1447-0756.2010.01464.x
  • Peer Reviewed
• [Journal Article] 子宮ポリープ状異型腺筋腫(atypical polypoid adenomyoma,APAM)の取り扱い (2011)
  • Author(s): 馬場 長、小西郁生
  • Journal Title: 産婦人科の進歩 Volume: 63巻2号
  • NAID: 130000904766
  • Peer Reviewed
• [Journal Article] Endometrial cancer implanted within a cesarean section scar. (2011)
  • Author(s): Baba T, Mandai M, Yamanishi Y, Suzuki A, Kang HS, Konishi I
  • Journal Title: J Obstet Gynaecol Res Volume: 37(3) Pages: 245-9
  • NAID: 120005595810
  • Peer Reviewed
• [Journal Article] The comprehensive assessment of local immune status of ovarian cancer by the clustering of multiple immune factors. (2011)
  • Author(s): Hamanishi J, Mandai M, Abiko K, Matsumura N, Baba T, Yoshioka Y, Kosaka K, Konishi I.
  • Journal Title: Clin Immunol Volume: 141(3) Pages: 338-47
  • NAID: 120003610113
  • Peer Reviewed
• [Journal Article] GPR54 Is a Target for Suppression of Metastasis in Endometrial Cancer (2011)
  • Author(s): Kang HS, Baba T, Mandai M, Matsumura N, Hamanishi J, Kharma B, Kondoh E, Yoshioka Y, Oishi S, Fujii N, Murphy SK, Konishi I
  • Journal Title: Mol Cancer Ther Volume: 10(4) Pages: 580-90
  • Peer Reviewed
• [Presentation] Tumor-associated-Lymphocytes attenuate tumor immunity to promote progression of serous endometrial cancer via STAT1 pathway (2013)
  • Author(s): Kharma B, Baba T, Mandai M, Matsumura N, Hamanishi J, Yamaguchi K, Konishi I
  • Organizer: Tumor-associated-Lymphocytes attenuate tumor immunity to promote progression of serous endometrial cancer via STAT1 pathway
  • Place of Presentation: Hyatt Regency Maui in Maui, HI
• [Presentation] Tumor-associated-Lymphocytes attenuate tumor immunity to promote progression of serous endometrial cancer via STAT1 pathway (2012)
  • Author(s): Kharma B, Baba T, Mandai M, Matsumura N, Hamanishi J, Yamaguchi K, Konishi I
  • Organizer: 14th Biennial Meeting of the International Gynecologic Cancer Society
  • Place of Presentation: Vancouver, Canada
• [Presentation] Tumor-associated-Lymphocytes attenuate tumor immunity to promote progression of serous endometrial cancer via STAT1 pathway (2012)
  • Author(s): Kharma B, Baba T, Mandai M, Matsumura N, Hamanishi J, Yamaguchi K, Konishi I
  • Organizer: 71st Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Sapporo, Japan
• [Presentation] Tumor-associated-Lymphocytes attenuate tumor immunity to promote progression of serous endometrial cancer via STAT1 pathway (2012)
  • Author(s): Kharma B, Baba T, Mandai M, Matsumura N, Hamanishi J, Yamaguchi K, Konishi I
  • Organizer: 64th Annual Meeting of the Japanese Society of Obstetrics and Gynecology
  • Place of Presentation: Kobe, Japan
• [Presentation] Utilization of genomic signatures to identify Fludarabine and Temsirolimus as candidate drugs with high efficacy to chemo-refractory endometrial cancers (2012)
  • Author(s): Baba T, Kharma B, Mandai M, Yoshioka Y,Hamanishi J, Matsumura N, Yamaguchi K,Murphy SK, Konishi I
  • Organizer: The 43rd SGO Annual Meeting on Women's Cancer
  • Place of Presentation: Austin, TX
• [Presentation] Fludarabine therapy in endometrial cancer: A possible alternative treatment (2011)
  • Author(s): Budiman Kharma, Tsukasa Baba, Hyun Sook Kang, Yumiko Yoshioka, Junzo Hamanishi, Noriomi Matsumura, Ken Yamaguchi, Masaki Mandai, Ikuo Konishi
  • Organizer: 2nd Biennial Meeting of Asian Society of Gynecologic Oncology (ASGO)
  • Place of Presentation: Ritz Carlton Hotel, Seoul(韓国)
• [Presentation] Attenuation of Tumor Immunity to Promote Progression of Serous Papillary Endometrial Cancer via STAT1 pathway
  • Author(s): Kharma B, Baba T, Konishi I
  • Organizer: 71st Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: ホテルロイトン札幌(北海道)
• [Presentation] 子宮頸がん術前化学療法の有用性 子宮頸癌治療における術前化学療法(NAC)の意義
  • Author(s): 馬場 長
  • Organizer: 第52回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: グランドプリンスホテル新高輪(東京都)
  • Invited
• [Presentation] 子宮頸癌に対する治療法～手術療法を中心に～
  • Author(s): 馬場 長
  • Organizer: 日本放射線技術学会平成24年度 市民公開シンポジウム
  • Place of Presentation: メルパルク京都(京都府)
  • Invited
• [Presentation] バイオインフォマティクスを利用した多剤耐性子宮体癌に対する有効薬剤の探索
  • Author(s): 馬場 長、Budiman Kharma、姜 賢淑、万代昌紀、濱西潤三、吉岡弓子、松村謙臣、小阪謙三、山口 建、小西郁生
  • Organizer: 第50回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 札幌コンベンションセンター(北海道)
• [Presentation] Utilization of genomic signatures to identify Fludarabine and Temsirolimus as candidate drugs with high efficacy to chemo-refractory endometrial cancers
  • Author(s): Tsukasa Baba, Budiman Kharma, Masaki Mandai, Yumiko Yoshioka, Junzo Hamanishi, Noriomi Matsumura, Ken Yamaguchi, Susan K Murphy, Ikuo Konishi
  • Organizer: 43rd The Annual Meeting on Women's Cancer（SGO: Society of Gynecologic Oncology）
  • Place of Presentation: Ａｕｓｔｉｎ Ｃｏｎｖｅｎｔｉｏｎ Ｃｅｎｔｅｒ(アメリカ合衆国)
• [Presentation] Fludarabine therapy in endometrial cancer: A possible alternative treatment
  • Author(s): Budiman Kharma, Tsukasa Baba, Hyun Sook Kang, Yumiko Yoshioka, Junzo Hamanishi, Noriomi Matsumura, Ken Yamaguchi, Masaki Mandai, Ikuo Konishi
  • Organizer: 第70回 日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
• [Book] 婦人科がん-最新の研究動向-「子宮体癌の検診・診断 腫瘍マーカー、バイオマーカー」 (2012)
  • Author(s): 馬場 長、小川まどか、小西郁生
  • Publisher: 日本臨床社
• [Book] 「子宮体癌の術前評価と手術方法の選択」, OGSnow 子宮体癌・卵巣癌の手術 基本術式と腫瘍進展に応じた戦略 (2011)
  • Author(s): 馬場 長、万代昌紀、小西郁生
  • Publisher: メジカルビュー社
• [Remarks] 研究案内
  • URL: http://www.kuhp.kyoto-u.ac.jp/~obgy/intro03.html