Efficacy of molecular targeting therapy and establishment of patient derived model in ARID1A-deficient ovarian clear cell carcinoma

• Project/Area Number: 17K11310
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: National Cancer Center Japan
• Principal Investigator: Tomoyasu Katoh 国立研究開発法人国立がん研究センター, 中央病院, 科長 (50224522)
• Co-Investigator(Kenkyū-buntansha): 荻原 秀明 国立研究開発法人国立がん研究センター, 研究所, 分野長 (40568953)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 卵巣明細胞がん / 婦人科腫瘍 / 卵巣がん / ARID1A / 精密医療 / 合成致死 / SLC7A11 / グルタチオン / クロマチンリモデリング / 患者由来細胞株 / 最適化がん治療 / APR-246 / BSO / 分子標的治療 / OCCC / PDX

Outline of Final Research Achievements

Ovarian clear cell caricinoma is refractory cancer. Previously, we found the hopeful drug APR-246 for ARID1A-deficient cancers. In this study, we aim to develop the patient-derived models and investigate the promising of APR-246 for ARID1A-deficient cancers. We revealed that ARID1A deficiency caused decrease of SLC7A11 expression and APR-246 treatment suppressed cells and tumors growth in patient-derived models.

Academic Significance and Societal Importance of the Research Achievements

卵巣明細胞がんは、化学療法の効きにくい難治性がんのため新しい治療薬の開発が求められていた。本研究では、ARID1A欠損がんに有望な新規薬剤が卵巣明細胞がんの半数の患者に対して有望であることを示した。APR-246は臨床試験薬であり、今後ARID1A欠損がんへの有効性を検証することで卵巣明細胞がん患者に対する新規薬剤として臨床応用されることが期待される。

Research Products

• [Journal Article] Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers. (2019)
  • Author(s): Ogiwara H, Takahashi K, Sasaki M, Kuroda T, Yoshida H, Watanabe R, Maruyama A, Makinoshima H, Chiwaki F, Sasaki H, Kato T, Okamoto A, Kohno T.
  • Journal Title: Cancer Cell Volume: 35 Issue: 2 Pages: 177-190
  • DOI: 10.1016/j.ccell.2018.12.009
  • Peer Reviewed / Open Access
• [Presentation] Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Ovarian Clear Cell Carcinoma (2019)
  • Author(s): Kazuaki Takahashi1,2, Hideaki Ogiwara1, Mariko Sasaki1, Takafumi Kuroda1,2, Hiroshi Yoshida3, Reiko Watanabe3, Ami Maruyama4,5, Hideki Makinoshima4, Fumiko Chiwaki6, Hiroki Sasaki6, Tomoyasu Kato7, Aikou Okamoto2 and Takashi Kohno1
  • Organizer: The 4th Asia-Pacific Ovarian Cancer Laparotomic and Laparoscopic Operation (APOLLO)
  • Int'l Joint Research / Invited
• [Presentation] SWI/SNFクロマチンリモデリング欠損がんにおける合成致死標的の探索 (2018)
  • Author(s): Hideaki Ogiwara, Mariko Sasaki, Kazuaki Takahashi, Takafumi Kuroda, Takashi Kohno
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] クロマチンリモデリング複合体欠損がんにおける合成致死治療法の開発 (2018)
  • Author(s): 荻原秀明、佐々木麻里子、河野隆志
  • Organizer: 2018年第41回日本分子生物学会年会
• [Presentation] Identification of Synthetic Lethal Targets in ARID1A-Deficient Ovarian Cancers (2018)
  • Author(s): Kazuaki Takahashi, Hideaki Ogiwara, Mariko Sasaki, Takafumi Kuroda, Reiko Watanabe, Hiroshi Yoshida, Tomoyasu Kato, Aikou Okamoto and Takashi Kohno
  • Organizer: IGCS 2018
  • Int'l Joint Research
• [Remarks] 代謝（メタボローム）を標的とした新たながん治療法を発見
  • URL: https://www.ncc.go.jp/jp/information/pr_release/2019/20190125/index.html
• [Remarks] 最適化がん治療の研究
  • URL: https://www.ncc.go.jp/jp/ri/division/genome_biology/project/020/20190125.html