Exploration of Therapeutic Target Pathways Involving DNA Repair Genes in High Grade Serous Ovarian Carcinoma

• Project/Area Number: 18K15304
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Asada Kayo 東京大学, 医学部附属病院, 届出研究員 (50805843)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 統合的ゲノム解析 / 卵巣高異型度漿液性癌 / 相同組換修復関連遺伝子変異 / PARP阻害剤 / 免疫チェックポイント阻害剤

Outline of Final Research Achievements

In this study, we aim to identify mutations and aberrant expression of genes involved in DNA damage repair based on the results of whole exon sequencing, RNA sequencing, and methylation array analysis in 78 cases of high grade serous ovarian carcinoma. The objectives of the research were to identify target factors, and to develop molecularly targeted therapies other than PARP inhibitors that focus on DNA repair mechanisms. As a result, we were able to show that SMYD2 selective inhibitors and immune checkpoint inhibitors may be alternative approaches to ovarian cancer treatment.

Academic Significance and Societal Importance of the Research Achievements

本研究では次世代シーケンサーを用いた解析結果より、卵巣高異型度漿液性癌におけるDNA傷害修復に関わる遺伝子の変異・発現異常を明らかにした。次に、卵巣がん治療に用いられるPARP阻害剤の治療標的として、BRCA1/2以外にヒストンメチルトランスフェラーゼであるSMYD2や、腫瘍免疫に着目した。結果、SMYD2選択的阻害剤や、免疫チェックポイント阻害剤が卵巣がん治療の代替手段となる可能性を示すことが出来た。
加えて、外来子宮鏡の有効性についての検討を進めており、子宮体がんの早期発見にdeep-learningを用いた外来子宮鏡でのAI診断が有用である可能性が示された。

Research Products

• [Journal Article] Automated system for diagnosing endometrial cancer by adopting deeplearning technology in hysteroscopy (2021)
  • Author(s): Takahashi Y, Sone K, Noda K, Yoshida K, Toyohara Y, Kato K, Inoue F, Kukita A, Taguchi A, Nishida H, Miyamoto Y, Tanikawa M, Tsuruga T, Iriyama T, Nagasaka K, Matsumoto Y, Hirota Y, Hiraike-Wada O, Oda K, Maruyama M, Osuga Y, Fujii T.
  • Journal Title: PLoS One Volume: 16 Issue: 3 March 2021 Pages: 1-13
  • DOI: 10.1371/journal.pone.0248526
  • Peer Reviewed / Open Access
• [Journal Article] Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma (2020)
  • Author(s): Matsushita Hirokazu、Hasegawa Kosei、Oda Katsutoshi、Yamamoto Shogo、Asada Kayo、Karasaki Takahiro、Yabuno Akira、Nishijima Akira、Nejo Takahide、Kobayashi Yukari、Sato Sho、Ikeda Yuji、Miyai Manami、Takahashi Yusuke、Yamaguchi Rui、Fujiwara Keiichi、Aburatani Hiroyuki、Kakimi Kazuhiro
  • Journal Title: Journal for ImmunoTherapy of Cancer Volume: 8 Issue: 1 Pages: e000375-e000375
  • DOI: 10.1136/jitc-2019-000375
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of biopsy by office hysteroscopy for endometrial cancer: A case report (2020)
  • Author(s): Sone Kenbun、Eguchi Satoko、Asada Kayo、Inoue Futaba、Miyamoto Yuichiro、Tanikawa Michihiro、Tsuruga Tetsushi、Mori?Uchino Mayuyo、Matsumoto Yoko、Hiraike?Wada Osamu、Oda Katsutoshi、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Molecular and Clinical Oncology Volume: 13 Issue: 2 Pages: 141-145
  • DOI: 10.3892/mco.2020.2053
  • Peer Reviewed / Open Access
• [Journal Article] Histone methyltransferase SMYD2 selective inhibitor LLY-507 in combination with poly ADP ribose polymerase inhibitor has therapeutic potential against high-grade serous ovarian carcinomas (2019)
  • Author(s): Kukita A, Sone K, Oda K, Hamamoto R, Kaneko S, Komatsu M, Wada M, Honjoh H, Kawata Y, Kojima M, Oki S, Sato M, Asada K, Taguchi A, Miyasaka A, Tanikawa M, Nagasaka K, Matsumoto Y, Wada-Hiraike O, Osuga Y, Fujii T
  • Journal Title: Biochem Biophys Res Commun Volume: 513 Issue: 2 Pages: 340
  • DOI: 10.1016/j.bbrc.2019.03.155
  • Peer Reviewed
• [Journal Article] The histone methyltransferase WHSC1 is regulated by EZH2 and is important for ovarian clear cell carcinoma cell proliferation (2019)
  • Author(s): Kojima Machiko、Sone Kenbun、Wada-Hiraike Osamu、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: BMC Cancer Volume: 19 Issue: 1 Pages: 455-455
  • DOI: 10.1186/s12885-019-5638-9
  • Peer Reviewed / Open Access
• [Presentation] Genomic characterization of high grade serous ovarian carcinoma (2018)
  • Author(s): Kayo Asada
  • Organizer: International Gynecologic Cancer Society
  • Int'l Joint Research / Invited