Foundation of chemotherapy for malignant glioma targeting mTOR

• Project/Area Number: 17K08304
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Niigata University
• Principal Investigator: EDA TAKEYOSHI 新潟大学, 医歯学総合病院, 薬剤師 (90772038)
• Co-Investigator(Kenkyū-buntansha): 棗田 学 新潟大学, 脳研究所, 助教 (00515728)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); 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); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Glioblastoma / mTOR / xenograft / drug repositioning / translational research / glioma / グリオーマ / 神経膠腫（グリオーマ） / 薬理学

Outline of Final Research Achievements

Glioblastoma (GBM) accounts for the majority of primary brain tumors. Multimodal therapy such as surgical removal, radiotherapy, and temozolomide (TMZ) chemotherapy is performed, whereas the prognosis is still poor. There is an urgent need to develop effective chemotherapy. In primary assessment, we performed a screened for drugs that regulated the proliferation and differentiation against GBM cell lines. Approved macrolides, clindamycin (CLD) reduced cell viability in cultures. Here, we demonstrated that CLD regulated the proliferation of GBM. CLD attenuated the phosphorylation of p70S6K in a dose dependent manner. These effects were synergistically enhanced by the combination with CLD and TMZ. In vivo experiment, repeated administration of CLD and TMZ suppressed tumor growth. These results indicate that CLD shows synergistic activity and sensitization in combination with conventional chemotherapy in xenografts.

Academic Significance and Societal Importance of the Research Achievements

CLDはGBM細胞に対し、高い抗腫瘍効果を示した。mTOR制御がその機序と考える。in vivo実験では、CLDとTMZ併用による作用を検証し、腫瘍は縮小を維持した。腫瘍制御におけるmTOR抑制については、フィードバック機構の存在が知られ、再発に関与するとされるが、CLDはTMZとの併用によりこれを回避している。GBM治療に重要な知見を提示する。
GBM治療への応用の際、CLDは既存薬であることから、ヒトでの安全性が確保されている。また、従来の抗悪性腫瘍薬とは作用機序も異なるため、骨髄抑制など強力な副作用を回避できる。薬価は分子標的薬と比べると安価で、医療費削減の一助となるなど意義は大きい。

Research Products

• [Journal Article] EGFRvIII Is Expressed in Cellular Areas of Tumor in a Subset of Glioblastoma (2019)
  • Author(s): Nozawa T , Okada M, Natsumeda M, Eda T, Abe H, Tsukamoto Y, Okamoto K, Oishi M, Takahashi H, Fujii Y, Kakita A
  • Journal Title: Neurologia medico-chirurgica Volume: 59 Issue: 3 Pages: 89-97
  • DOI: 10.2176/nmc.oa.2018-0078
  • NAID: 130007612662
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] mTORシグナルを標的とした悪性グリオーマに対する新規化学療法の基盤研究 (2019)
  • Author(s): 江田岳誉、金丸優、岡田正康、棗田学、大石誠、藤井幸彦
  • Organizer: 第92回日本薬理学会年会