The investigation of new treatment for ovarian clear cell carcinoma with TOP2A amplification

• Project/Area Number: 16H06907
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Obstetrics and gynecology
• Research Institution: Kyoto University
• Principal Investigator: Murakami Ryusuke 京都大学, 医学研究科, 特定病院助教 (40782363)
• Project Period (FY): 2016-08-26 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 卵巣明細胞癌 / 染色体17番長腕増幅 / シスプラチン耐性 / PDK2 / 染色体17番長腕 / プラチナ抵抗性 / stemness / TP53 / TOP2A

Outline of Final Research Achievements

Ovarian clear cell carcinoma (CCC) has poor prognosis owing to its chemoresistance. Here we aimed to identify a biomarker of this drug resistance and the therapeutic target of CCC. Whole exome sequencing and expression microarray were conducted using 39 CCC clinical samples and 13 CCC cell lines. IC50 values and apoptosis of 13 CCC cell lines against cisplatin were measured by cleaved caspase-3. Chr17q21-24 amplification correlated positively with IC50 values for cisplatin in 13 CCC cell lines (r>0.4). The expression levels of 59 genes located on chr17q21-24 are positively correlated with Chr17q21-24 amplification in 13 CCC cell lines and 18 CCC patients (r>0.4). Of these 59 genes, we focused on pyruvate dehydrogenase kinase isoform 2(PDK2). A PDK inhibitor and suppression of PDK2 decreased the IC50 values for cisplatin by increasing cleaved caspase-3 expression. PDK2 inhibition is a promising therapeutic strategy against CCC.

Research Products

• [Presentation] Is the mesenchymal transition subtype more responsive to dose dense taxane chemotherapy combined with carboplatin (ddTC) than to conventional taxane and carboplatin chemotherapy (TC) in high grade serous ovarian carcinoma? A survey of Japanese Gynecology Oncology Group study (JGOG3016A1) (2017)
  • Author(s): Ryusuke Murakami, Noriomi Matsumura, Hiroshi Tanabe, Hirofumi Michimae, Mayu Yunokawa, Haruko Iwase, Motoi Sasagawa, Toshiaki Nakamura, Osamu Tokuyama, Masashi Takano, Toru Sugiyama, Takashi Sawasaki, Seiji Isonishi, Kazuhiro Takehara, Hidekatsu Nakai, Aikou Okamoto, Masaki Mandai, Ikuo Konishi
  • Organizer: ASCO2017, J Clin Oncol 35, 2017
  • Int'l Joint Research
• [Presentation] PDK2 contributes to the platinum resistance of ovarian clear cell carcinoma accompanied by chromosome 17q amplification (2017)
  • Author(s): Sachiko Kitamura, Ken Yamaguchi, Ryusuke Murakami, Kaoru Abiko Junzo Hamanishi, Tsukasa Baba, Noriomi Matsumura, Masaki Mandai
  • Organizer: 日本癌学会
• [Presentation] The investigation for overcoming platinum resistance of Ovarian Clear Cell Carcinoma with chromosome 17q amplification (2016)
  • Author(s): Sachiko Kitamura, Ken Yamaguchi, Ryusuke Murakami, Kaoru Abiko, Junzo Hamanishi, Tsukasa Baba, Noriomi Matsumura
  • Organizer: がんプロ 5大学連携 香港合同教育セミンター
  • Place of Presentation: プリンスオブウェールズ病院, Chinese University Hong Kong
  • Year and Date: 2016-10-28
  • Int'l Joint Research