Development of therapeutics targeting DNA damage repair pathway in uterine neoplasms

• Project/Area Number: 16K21330
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology; Tumor therapeutics
• Research Institution: The University of Tokyo
• Principal Investigator: Miyasaka Aki 東京大学, 医学部附属病院, 登録研究員 (10754997)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 子宮腫瘍 / クリニカルシークエンス / 相同組換修復 / PARP阻害薬 / 子宮体癌 / BRCA / MED1 / DNA修復 / 化学療法 / 放射線 / ATM阻害薬 / 分子標的薬 / 放射線照射 / DNA修復経路 / シグナル伝達経路

Outline of Final Research Achievements

Uterine sarcomas are rare malignant uterine neoplasms. Their rarity and histopathological diversity have contributed to the lack of consensus on risk factors for poor outcome and optimal treatment. Genome sequencing is a comprehensive method for analyzing entire genomes, which is a powerful tool for elucidating pathological conditions and developing treatments. “Onco-panel for gene profiling” is a sequencing that can comprehensively analyze about mutations of five hundred at a time using a next-generation sequencing. Whether the found mutations were clinically significant was judged from the gene database. It has been suggested that treatment targeting the DNA damage repair pathway such as PARP inhibitor may be effective for uterine sarcoma.

Academic Significance and Societal Importance of the Research Achievements

子宮肉腫は稀少であり、その病理病態が未解明な腫瘍である。治療法は確立されておらず、予後も不良である。肉腫の診断及び新規治療の開発に関して、治療法の開発は急務である。全エクソンシークエンス・全ゲノムシークエンス・RNA-Seq等を個別の症例において適宜行うことにより、ドライバー変異や治療標的になりうる体細胞変異の検索を行うことが可能である。個々の症例の蓄積が、稀少疾患に最適なクリニカルシークエンス検査の構築や新規治療の開発につながる。その導入としての今回の研究は学術的、および社会的にも有意義であると考えられる。

Research Products

• [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: in press Issue: 2 Pages: 30555-8
  • DOI: 10.1016/j.bbrc.2019.03.155
  • Peer Reviewed
• [Journal Article] Kaempferol, a natural dietary flavonoid, suppresses 17β?estradiol?induced survivin expression and causes apoptotic cell death in endometrial cancer (2018)
  • Author(s): Chuwa Agapiti、Sone Kenbun、Oda Katsutoshi、Tanikawa Michihiro、Kukita Asako、Kojima Machiko、Oki Shinya、Fukuda Tomohiko、Takeuchi Makoto、Miyasaka Aki、Kashiyama Tomoko、Ikeda Yuji、Nagasaka Kazunori、Mori?Uchino Mayuyo、Matsumoto Yoko、Wada?Hiraike Osamu、Kuramoto Hiroyuki、Kawana Kei、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Oncology Letters Volume: 16 Pages: 6195-6201
  • DOI: 10.3892/ol.2018.9340
  • Peer Reviewed / Open Access
• [Presentation] A histone methyltransferase SMYD2 selective inhibitor（LLY-507）in combination with a PARP inhibitor（Olaparib）have a therapeutic potential for high-grade serous ovarian carcinomas (2019)
  • Author(s): Asako Kukita, et al
  • Organizer: 第71回 産科婦人科学会学術集会
• [Presentation] Clinical sequencing by Todai OncoPanel（TOP）for uterine sarcomas (2019)
  • Author(s): Hirofumi Inaba, et al
  • Organizer: 第71回 産科婦人科学会学術集会