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

2012 Fiscal Year Final Research Report

• 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
• Keywords: 婦人科腫瘍学

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
  • DOI: 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(3) Pages: 576-82
  • DOI: doi:10.1097/IGC.0b013e3182849e36
  • 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(6) Pages: 1363-74
  • DOI: doi:10.1158/1078-0432.CCR-12-2199
  • Peer Reviewed
• [Journal Article] Clinical management of atypical polypoid adenomyoma of the uterus. A clinicopathological review of 29 cases (2012)
  • 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) Pages: 54-7
  • DOI: doi:10.1016/j.ygyno.2012.12.040
  • 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) Pages: 214-21
  • DOI: doi:10.1007/s00795-011-0562-3
  • Peer Reviewed
• [Journal Article] Adenoid cystic carcinoma of skene glands: arare 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) Pages: 596-600
  • DOI: 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) Pages: 375-380
  • DOI: doi:10.3892/ol.2012.770
  • Peer Reviewed
• [Journal Article] Advanced extragonadal yolk sac tumor serially followed up with 18F-fluorodexyglucose-PET/CT and serum AFP (2012)
  • Author(s): Baba T, Su S, Umeoka S, Abiko K, Nakamoto Y, Mandai M, Matsumura N,Konishi I
  • Journal Title: J Obstet Gynaecol Res Volume: 38(3) Pages: 605-9
  • DOI: doi:10.1111/j.1447-0756.2011.01752.x
  • Peer Reviewed
• [Journal Article] A case of solitary fibrous tumor arising slowly in 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) Pages: 884-8
  • DOI: doi:10.1111/j.1447-0756.2011.01792.x
  • Peer Reviewed
• [Journal Article] A Primary Squamous Cell Carcinoma of Fallopian Tube Accompanied with Gastric Metaplasia of Female Genital TractCase 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) Pages: 1106-11
  • DOI: doi:10.1111/j.1447-0756.2010.01464.x
  • 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
  • Year and Date: 20130221-25
• [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
  • Year and Date: 20121013-16
• [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
  • Year and Date: 20120919-21
• [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
  • Year and Date: 20120413-15
• [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
  • Year and Date: 20120324-27