Development of Molecular Targeted Therapy for Oral Cancer by Targeting Sphingosine Kinase

• Project/Area Number: 18K09787
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Osaka University
• Principal Investigator: Hamada Masakazu 大阪大学, 歯学研究科, 助教 (80506361)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: オートファジー / 分子標的治療 / Sphingosine kinase / 口腔癌 / SphK1 / アポトーシス

Outline of Final Research Achievements

In addition to necrosis and apoptosis, cell death is mediated by autophagy. Treatment of human oral squamous cell carcinoma cells with PF-543 induced necrosis, apoptosis and autophagy, and the combination of PF-543 and autophagy inhibitor enhanced cell death more than PF-543 alone, suggesting that autophagy may play a role in cell survival. Research on inhibitors of SphK is ongoing, and further development of molecular targeted therapy targeting SphK is expected through the development of new drugs and elucidation of their mechanisms of action.

Academic Significance and Societal Importance of the Research Achievements

ヒト口腔扁平上皮癌細胞をSphK1阻害薬であるPF-543で処理すると、ネクローシス、アポトーシスならびにオートファジーが誘導された。さらにPF-543とオートファジー阻害剤の併用にて、PF-543単剤よりも細胞死は増強されたことから、オートファジーは細胞生存に働いている可能性が示唆された。SphKに対する阻害薬の研究は進行しており、S1Pシグナルによるオートファジーの細胞死制御機序の解明を通して，副作用の少ないより効率的なSphKをターゲットとした分子標的治療のさらなる発展が期待出来る。

Research Products

• [Journal Article] Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma (2020)
  • Author(s): Yura Y, Masui A, Hamada M.
  • Journal Title: Cancers Volume: 12 Issue: 8 Pages: 2062-2062
  • DOI: 10.3390/cancers12082062
  • Peer Reviewed / Open Access
• [Journal Article] Efficient Delivery and Replication of Oncolytic Virus for Successful Treatment of Head and Neck Cancer (2020)
  • Author(s): Hamada M, Yura Y.
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 19 Pages: 7073-7073
  • DOI: 10.3390/ijms21197073
  • Peer Reviewed / Open Access
• [Journal Article] Current treatment, particle radiotherapy, and boron neutron capture therapy for advanced oral cancer in patients (2019)
  • Author(s): Yura Yoshiaki、Tada Shinya、Fujita Yusei、Hamada Masakazu
  • Journal Title: Oral Science International Volume: 16 Pages: 49-68
  • Peer Reviewed
• [Journal Article] 腫瘍融解性ウイルス療法とプロテオミクス (2019)
  • Author(s): 由良義明，濱田正和．
  • Journal Title: 炎症と免疫 Volume: 28 Pages: 26-30
  • Peer Reviewed
• [Presentation] TCGAデータの解析に基づく口腔癌におけるSphK1、2 and CERKの標的化 (2020)
  • Author(s): 濱田正和、西山今日子、鵜澤成一
  • Organizer: 日本癌学会
• [Presentation] Targeting for sphingosine kinase 1 in oral squamous cell carcinoma based on analysis of TCGA data (2019)
  • Author(s): Hamada M, Uzawa N.
  • Organizer: 日本癌学会
• [Presentation] Bidirectional effect of autophagy on sphingosine kinase I inhibitor PF543-induced cell death of oral squamous cell carcinoma cells (2019)
  • Author(s): Hamada M, Kameyama H, Iwai S, Uzawa N
  • Organizer: 11th Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association
  • Int'l Joint Research
• [Presentation] SphK1 inhibitor PF-543 induces autophagy regulated by ROS generation in oral squamous cell carcinoma cells (2018)
  • Author(s): Hamada M, Iwai S, Uzawa N
  • Organizer: 日本癌学会