Development of new treatments for neuroblastoma based on the synthetic lethality

• Project/Area Number: 15K18442
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Nagoya University
• Principal Investigator: KIYONARI Shinichi 名古屋大学, 医学系研究科, 特任助教 (70570836)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 合成致死 / 神経芽腫

Outline of Final Research Achievements

MYCN gene amplification clearly correlates with poor prognosis in patients with pediatric cancer, neuroblastoma. Recently, synthetic lethal (SL) approaches are emerging as a promising strategy for MYCN-amplified neuroblastoma therapy. Therefore, we performed a genome-wide shRNA library screening to identify new candidate genes. Based on our experimental validations using siRNA and chemical inhibitors, some enzymes involved in nucleic acid metabolism were proposed to be new SL targets. Our result suggest that repositioning of existing agents would be worth considering as a new therapeutic strategy. Moreover, finding new chemical inhibitors of new SL targets is important for therapeutic development.

Research Products

• [Journal Article] Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes. (2017)
  • Author(s): 1.Su Z, Kishida S, Tsubota S, Sakamoto K, Cao D, Kiyonari S, Ohira M, Kamijo T, Narita A, Xu Y, Takahashi Y, Kadomatsu K.
  • Journal Title: Oncotarget Volume: 8 Issue: 63 Pages: 106296-106310
  • DOI: 10.18632/oncotarget.22435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma (2017)
  • Author(s): 2.Tsubota S, Kishida S, Shimamura T, Ohira M, Yamashita S, Cao D, Kiyonari S, Ushijima T, Kadomatsu K.
  • Journal Title: Cancer Res. Volume: 77 Issue: 19 Pages: 5259-5271
  • DOI: 10.1158/0008-5472.can-16-3144
  • Peer Reviewed
• [Presentation] Genome-wide RNAi screen identifies new synthetic lethal interactions in MYCN-amplified neuroblastoma cells (2017)
  • Author(s): Shinichi Kiyonari、Kenji Kadomatsu
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Remarks] 名古屋大学大学院医学系研究科生物化学講座分子生物学ホームページ
  • URL: https://www.med.nagoya-u.ac.jp/biochem/