Development of individualized therapy by elucidation of molecular mechanisms for hypermutation phenotype induced by treatment with alkylating agents in glioma

• Project/Area Number: 18K09004
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Kyorin University
• Principal Investigator: Noguchi Akio 杏林大学, 医学部, 准教授 (30311971)
• Co-Investigator(Kenkyū-buntansha): 永根 基雄 杏林大学, 医学部, 教授 (60327468)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 神経膠腫 / 遺伝子異常 / 高度点変異誘導 / アルキル化剤 / 薬剤耐性 / 個別化治療

Outline of Final Research Achievements

This study aimed to elucidate molecular mechanisms for developing hypermutation after treatment with temozolomide (TMZ) or ACNU in glioma. Human glioma, MGMT-null cell lines, U251 and LNZ308, MGMT-forced expressing subline were used. TMZ- or ACNU-resistant sublines were also developed by continuous dose-elevating exposure of cells to the drugs. Both TMZ and ACNU resistant cells expressed MGMT whereas their expressions of mismatch repair proteins were not altered. MLPA and Cancer Gene Panel analyses disclosed no additional or new genetic alterations identified in any of resistant sublines. More efforts need to be pursued to clarify the hypermutation phenotype in future studies.

Academic Significance and Societal Importance of the Research Achievements

本研究では、TMZ及びACNUなどの薬剤による神経膠腫細胞におけるhypermutator形質の発生度や分子機序を解析し、薬剤の種類や腫瘍細胞の背景形質や遺伝子異常のパターンによる相違を明らかにすることで、TMZ治療におけるhypermutator化の危険因子を探索し、TMZ治療の良好な対象群を解明することを目的とした。今回の一連の実験では薬剤耐性獲得とhypermutationの一義的な関連は検証できず、IDH変異の有無を考慮に入れるなど別角度での実験系構築が必要であることが示唆された。本機序が明らかとなれば、神経膠腫治療に新たな指標が導入され、治療向上に寄与することが期待される。

Research Products

• [Journal Article] Reduced H3K27me3 levels in diffuse gliomas: association with 1p/19q codeletion and difference from H3K27me3 loss in malignant peripheral nerve sheath tumors (2021)
  • Author(s): Kitahama K, Iijima S, Sumiishi A, Hayashi A, Nagahama K, Saito K, Sasaki N, Kobayashi K, Shimizu S, Nagane M, Shibahara J
  • Journal Title: Brain Tumor Pathol Volume: 38 Issue: 1 Pages: 23-29
  • DOI: 10.1007/s10014-020-00382-y
  • Peer Reviewed
• [Journal Article] Survival in patients with glioblastoma at a first progression does not correlate with isocitrate dehydrogenase (IDH)1 gene mutation status (2021)
  • Author(s): Tabei Y, Kobayashi K, Saito K, Shimizu S, Suzuki K, Sasaki N, Shiokawa Y, Nagane M
  • Journal Title: Jpn J Clin Oncol Volume: 51 Issue: 1 Pages: 45-53
  • DOI: 10.1093/jjco/hyaa162
  • Peer Reviewed / Open Access
• [Journal Article] TERT promoter mutation confers favorable prognosis regardless of 1p/19q status in adult diffuse gliomas with IDH1/2 mutations (2020)
  • Author(s): Arita H, Matsushita Y, Machida R et al.
  • Journal Title: Acta Neuropathologica Communications Volume: 8 Issue: 1 Pages: 201-201
  • DOI: 10.1186/s40478-020-01078-2
  • Peer Reviewed / Open Access
• [Journal Article] Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone (2020)
  • Author(s): Natsume A, Nagane M, Wakabayashi T, et al.
  • Journal Title: J Neurooncol Volume: May 4 Issue: 1 Pages: 17-27
  • DOI: 10.1007/s11060-020-03505-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical and molecular genetic feature of cerebellar glioblastoma (2019)
  • Author(s): Iijima S, Saito K, Shimizu S, Kobayashi K, Shimada D, Matsumoto Y, Shiokawa Y, Nagane M
  • Journal Title: Neuro-Oncology Advances Volume: 1 Issue: Supplement_2 Pages: ii37-ii38
  • DOI: 10.1093/noajnl/vdz039.170
  • Open Access
• [Journal Article] Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas (2019)
  • Author(s): Guerreiro Stucklin AS, Ichimura K, Nagane M, Bouffet E, Taylor M, Tabori U, Hawkins C, et al.
  • Journal Title: Nature Comm Volume: 10(1) Issue: 1 Pages: 4343-4343
  • DOI: 10.1038/s41467-019-12187-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Safety and effectiveness of bevacizumab in Japanese patients with malignant glioma: a post-marketing surveillance study (2019)
  • Author(s): Nagane M, Hayashi Y, Shimizu A, Ura M, Nishikawa R
  • Journal Title: Jpn J Clin Oncol Volume: 49 Issue: 11 Pages: 1016-1023
  • DOI: 10.1093/jjco/hyz125
  • Peer Reviewed
• [Journal Article] Reduced Neoantigen Expression Revealed by Longitudinal Multiomics as a Possible Immune Evasion Mechanism in Glioma. (2019)
  • Author(s): Nejo T, Matsushita H, Karasaki T, Nomura M, Saito K, Tanaka S, Takayanagi S, Hana T, Takahashi S, Kitagawa Y, Koike T, Kobayashi Y, Nagae G, Yamamoto S, Ueda H, Tatsuno K, Narita Y, Nagane M, Ueki K, Nishikawa R, Aburatani H, Mukasa A, Saito N, Kakimi K.
  • Journal Title: Cancer Immunol Res Volume: in press Issue: 7 Pages: 1148-1161
  • DOI: 10.1158/2326-6066.cir-18-0599
  • Peer Reviewed
• [Journal Article] DNA demethylation is associated with malignant progression of lower-grade gliomas (2019)
  • Author(s): Nomura Masashi、Saito Kuniaki、Aihara Koki、Nagae Genta、Yamamoto Shogo、Tatsuno Kenji、Ueda Hiroki、Fukuda Shiro、Umeda Takayoshi、Tanaka Shota、…、Narita Yoshitaka、Nagane Motoo、Nishikawa Ryo、Ueki Keisuke、Saito Nobuhito、Aburatani Hiroyuki、Mukasa Akitake
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 1903-1903
  • DOI: 10.1038/s41598-019-38510-0
  • Peer Reviewed / Open Access
• [Journal Article] A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma. (2018)
  • Author(s): Narita Y, Arakawa Y, Yamasaki F, Nishikawa R, Aoki T, Kanamori M, Nagane M, Kumabe T, Hirose Y, Ichikawa T, Kobayashi H, Fujimaki T, Goto H, Takeshima H, Ueba T, Abe H, Tamiya T, Sonoda Y, Natsume A, Kakuma T, Sugita Y, Komatsu N, Yamada A, Sasada T, Matsueda S, Shichijo S, Itoh K, Terasaki M.
  • Journal Title: Neuro Oncol. Volume: 21 Issue: 3 Pages: 348-359
  • DOI: 10.1093/neuonc/noy200
  • Peer Reviewed / Open Access
• [Presentation] 膠芽腫の治療開発：Temozolomideと課題 (2020)
  • Author(s): 永根基雄
  • Organizer: 第38回日本脳腫瘍学会学術集会
  • Invited
• [Presentation] Challenges in optimization of MGMT promoter methylation assays for development of companion diagnosis in glioblastoma (2019)
  • Author(s): Motoo Nagane, Kuniaki Saito, Keiichi Kobayashi, Saki Shimizu, Nobuyoshi Sasaki, Yuki Yamagishi, Yoshiaki Shiokawa
  • Organizer: 24th Annual Meeting of the Society for Neuro-Oncology
  • Int'l Joint Research
• [Presentation] 膠芽腫に対するコンパニオン診断法としてのMGMT遺伝子メチル化の解析法最適化における課題 (2019)
  • Author(s): 永根基雄，齊藤 邦昭，小林 啓一，清水 早紀，島田 大輔，松本 淑恵，佐々木 重嘉，久米 賢，飯島 昌平，山岸 夢希，塩川 芳昭
  • Organizer: 日本脳神経外科学会 第78回 学術集会
• [Presentation] Phase 1/2 study of depatuxizumab mafodotin (ABT-414) monotherapy or combination with temozolomide in Japanese patients with/without EGFR-amplified recurrent glioblastoma (2019)
  • Author(s): Yoshitaka Narita, Yoshihiro Muragaki, Takashi Maruyama, Naoki Kagawa, Katsunori Asai, Junichiro Kuroda, Kazuhiko Kurozumi, Motoo Nagane, Masahid Matsuda, Keisuke Ueki, Christopher Joseph Ocampo, Ikiru Matsumoto, Reiko Odagawa, Yasuko Nishimura, Kazuhiko Mishima
  • Organizer: 2019 ASCO Annual Meeting
  • Int'l Joint Research
• [Presentation] Mutation change after temozolomide treatment in primary glioblastoma (2018)
  • Author(s): Motoo Nagane, Kuniaki Saito, Keiichi Kobayashi, Saki Shimizu, Yoshiaki Shiokawa
  • Organizer: The 15th Meeting of the Asian Society for Neuro-Oncology
  • Int'l Joint Research
• [Presentation] Detailed analysis of mutation change after treatment in glioblastoma (2018)
  • Author(s): Nagane M, Saito K, Shimizu S, Nozaki E, Kobayashi K, Kume S, Chiba T, Shibahara J, Shiokawa Y
  • Organizer: 13th European Association of Neuro-Oncology
  • Int'l Joint Research
• [Presentation] IDH gene mutation status plays no impact on survival in patients with glioblastoma at a first progression (2018)
  • Author(s): Motoo Nagane, Yusuke Tabei, Keiichi Kobayashi, Kuniaki Saito, Saki Shimizu, Yoshiaki Shiokawa
  • Organizer: 22nd International Conference on Brain Tumor Research and Therapy
  • Int'l Joint Research / Invited