Functional analysis of specific genetic alterations in primary central nervous system lymphomas and development of novel molecular targeted therapies

• Project/Area Number: 16H05442
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Kyorin University
• Principal Investigator: Nagane Motoo 杏林大学, 医学部, 教授 (60327468)
• Co-Investigator(Kenkyū-buntansha): 市村 幸一 国立研究開発法人国立がん研究センター, 研究所, 分野長 (40231146) ; 富山 新太 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 病院 脳神経外科, 講師 (40385810) ; 中村 大志 横浜市立大学, 医学部, 助教 (60771615) ; 立石 健祐 横浜市立大学, 医学部, 助教 (00512055)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2019: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2017: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 中枢神経系悪性リンパ腫 / PIM1 / BAD / NF-kB / 二次性中枢神経系悪性リンパ腫 / 遺伝子変異解析 / 分子標的治療 / 部位特異的変異導入法 / 脳腫瘍 / 遺伝子解析 / 転移機序 / シグナル伝達 / 分子標的知慮

Outline of Final Research Achievements

We performed in vitro analysis of the PIM1 mutation, especially the K115N mutation which was associated with poor prognosis in primary central nervous system lymphoma (PCNSL). The K115N mutation was revealed to drive Bcl-2 associated death promotor (BAD) phosphorylation through augmented cytosolic localization of Pim-1, and its role in the inhibition of cell death was suggested. It was also revealed that activation of the NF-kB pathway is a promising therapeutic target in PCNSL, using originally established cell lines. Genetic analysis with paired samples from CNS and systemic lesions in individual patients revealed potential common genetic alterations favorable for CNS involvement.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果から、PCNSLにほぼ必発するにもかかわらず、その意義が明らかではなかったPIM1 変異の少なくとも一部は、PCNSLの発生に関与する可能性が示唆された。またNF-kB標的治療のproof-of-conceptが示され、今後Pim-1 やNF-kBを治療標的とした新規の治療開発が期待され、難治疾患であるPCNSLの予後改善に貢献しうる成果である。

Research Products

• [Journal Article] Consecutive single-institution case series of primary central nervous system lymphoma treated by R-MPV or high-dose methotrexate monotherapy (2020)
  • Author(s): Sasaki N, Kobayashi K, Saito K, Shimizu S, Suzuki K, Lee J, Yamagishi Y, Shibahara J, Takayama N, Shiokawa Y, Nagane M
  • Journal Title: Jpn J Clin Oncol Volume: inpress Issue: 9 Pages: 1-11
  • DOI: 10.1093/jjco/hyaa073
  • Peer Reviewed
• [Journal Article] Detection of t(14;18)(q32;q21) for IgH/BCL2 in CNS tumor-like lesions with chronic perivascular inflammation (2020)
  • Author(s): Shishido-Hara Y, Yazawa T, Kojima K, Ishii J, Kobayashi K, Lee JH, Chiba T, Sumiishi A, Tsuchiya K, Uchihara T, Shiokawa Y, Takayama N, Nagane M, Kamma H
  • Journal Title: Clinical and Experimental Neuroimmunology Volume: inpress
  • Peer Reviewed
• [Journal Article] 中枢神経系原発びまん性大細胞型B細胞リンパ腫 (2020)
  • Author(s): 永根基雄
  • Journal Title: 血液内科 Volume: 80 Pages: 623-635
• [Journal Article] Redox Reaction and Clinical Outcome of Primary Diffuse Large B-cell Lymphoma of the Central Nervous System: Prognostic Role of Metabolic and Textural Parameters of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET/computed Tomography in a Small Patient Cohort (2020)
  • Author(s): Tsuchiya J, Tateishi K et al.
  • Journal Title: Nucl Med Commun Volume: inpress
  • Peer Reviewed
• [Journal Article] Mechanisms of cell death inhibition through change in subcellular localization of Pim-1 by PIM1 gene mutation recurrently found in primary central nervous system lymphoma (2019)
  • Author(s): Sasaki N, Ichimura K, Nagane M, Tomiyama A
  • Journal Title: Neuro-Oncology Advances Volume: 1 Issue: Supplement_2 Pages: ii34-ii34
  • DOI: 10.1093/noajnl/vdz039.154
  • Peer Reviewed
• [Journal Article] Functional outcomes of initial treatments for patients with primary central nervous system lymphoma assessed by ADL and neurocognitive function (2019)
  • Author(s): Taku M, Kobayashi K, Yamagishi Y, Saito K, Shimada D, Matsumoto Y, Kikuchi H, Yamada S, Shiokawa Y, Nagane M, Okajima Y
  • Journal Title: Neuro-Oncology Advances Volume: 1 Issue: Supplement_2 Pages: ii30-ii30
  • DOI: 10.1093/noajnl/vdz039.137
• [Journal Article] Multiagent immunochemotherapy, R-MPV-A, for patients with secondary central nervous system lymphoma (2019)
  • Author(s): Nagane M, Kobayashi K, Saito K, Shimada D, Matsumoto Y, Iijima S, Sasaki N, Yamagishi Y, Takayama N, Shiokawa Y
  • Journal Title: Neuro-Oncology Advances Volume: 1 Issue: Supplement_2 Pages: ii32-ii32
  • DOI: 10.1093/noajnl/vdz039.145
  • Peer Reviewed
• [Journal Article] NF-kB canonical pathway activation drives glycolysis and tumor progression in primary central nervous system lymphoma (2019)
  • Author(s): Tateishi K, Sasaki N, Kawazu M, Miyake Y, Nakamura T, Yoshii Y, Matsushita Y, Miyake S, Sasame J, Yamanaka S, Yamamoto T, Wakimoto H, Nagane M, Ichimura K
  • Journal Title: Neuro-Oncology Advances Volume: 1 Issue: Supplement_2 Pages: ii10-ii10
  • DOI: 10.1093/noajnl/vdz039.045
  • Peer Reviewed
• [Journal Article] Hepatosplenic gamma-delta T cell lymphoma involving the brain (2018)
  • Author(s): Iijima S, Chiba T, Maruyama K, Saito K, Kobayashi K, Yamagishi Y, Shibahara J, Takayama N, Shiokawa Y, Nagane M
  • Journal Title: World Neurosurg Volume: 118 Pages: 139-142
  • DOI: 10.1016/j.wneu.2018.07.048
  • Peer Reviewed
• [Journal Article] 中枢神経系悪性リンパ腫の治療開発－多剤併用薬物療法及び新規分子標的治療薬 (2018)
  • Author(s): 永根基雄
  • Journal Title: 最新医学 Volume: 73 Pages: 1441-1449
• [Journal Article] MyD88 Mutation in Elderly Predicts Poor Prognosis in Primary Central Nervous System Lymphoma: Multi-Institutional Analysis (2018)
  • Author(s): Takano Shingo、Hattori Keiichiro、Ishikawa Eiichi、Narita Yoshitaka、Iwadate Yasuo、Yamaguchi Fumio、Nagane Motoo、Akimoto Jiro、Oka Hidehiro、Tanaka Satoshi、Sakata Mamiko、Matsuda Masahide、Yamamoto Tetsuya、Chiba Shigeru、Matsumura Akira
  • Journal Title: World Neurosurgery Volume: 112 Pages: e69-e73
  • DOI: 10.1016/j.wneu.2017.12.028
  • Peer Reviewed / Open Access
• [Journal Article] Black hairy tongue after chemotherapy for malignant brain tumors (2017)
  • Author(s): Yamagishi Y, Maruyama K, Kobayashi K, Kume S, Sasaki N, Yokoya S, Saito K, Shiokawa Y, and Nagane M
  • Journal Title: Acta Neurochir Volume: 159 Issue: 1 Pages: 169-172
  • DOI: 10.1007/s00701-016-3036-5
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide DNA methylation profiles identifies primary central nervous system lymphomas as a distinct entity from systemic diffuse large B-cell lymphomas (2017)
  • Author(s): Nakamura T, Yamashita S, Fukumura K, Tanaka K, Nagane M, Narita Y, Mano H, Ushijima T, Ichimura K
  • Journal Title: Acta Neuropathol Volume: 133 Issue: 2 Pages: 321-324
  • DOI: 10.1007/s00401-016-1664-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic factors for primary central nervous system lymphomas treated with high-dose methotrexate-based chemo-radiotherapy (2017)
  • Author(s): Lee Jeunghun、Shishido-Hara Yukiko、Suzuki Kaori、Shimizu Saki、Kobayashi Keiichi、Kamma Hiroshi、Shiokawa Yoshiaki、Nagane Motoo
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 47 Issue: 10 Pages: 925-934
  • DOI: 10.1093/jjco/hyx098
  • Peer Reviewed / Open Access
• [Journal Article] Combined immunochemotherapy, R-MPV-A, with reduced or deferred radiotherapy for PCNSL improves survival with favorable performance and cognitive function (abst #ACTR-23) (2016)
  • Author(s): Nagane M, Keiichi K, Saito K, Sasaki N, Kume S, Yamagishi Y, Shimizu S, Suzuki K, Shiokawa Y
  • Journal Title: Neuro-Oncology Volume: 18 (suppl 6)
  • Peer Reviewed
• [Presentation] Phase 1/2 study of tirabrutinib (ONO/GS-4059), a next-generation Bruton’s Tyrosine Kinase (BTK) inhibitor, monotherapy in patients with relapsed/refractory primary central nervous system lymphoma (PCNSL) (2019)
  • Author(s): Motoo Nagane, Yoshitaka Narita, Kazuhiko Mishima, Yasuhito Terui, Yoshiki Arakawa, Hajime Yonezawa, Katsunori Asai, Noriko Fukuhara, Kazuhiro Sugiyama, Naoki Shinojima, Junsaku Kitagawa, Arata Aoi, Ryo Nishikawa
  • Organizer: Annual Meeting of American Society of Hematology
  • Int'l Joint Research
• [Presentation] 二次性中枢神経系悪性リンパ腫に対するR-MPV-A療法の治療成績 (2019)
  • Author(s): 永根基雄，小林啓一，齊藤邦昭，島田大輔，松本淑恵，飯島昌平，佐々木重嘉，山岸夢希，高山信之，塩川芳昭
  • Organizer: 第37回日本脳腫瘍学会学術集会
• [Presentation] Standard of care and novel therapeutic insights for primary central nervous system lymphoma (2019)
  • Author(s): Motoo Nagane
  • Organizer: The 16th Meeting of the Asian Society for Neuro-Oncology
  • Int'l Joint Research / Invited
• [Presentation] ト由来中枢神経原発悪性リンパ腫細胞株を用いた腫瘍発生進展機構の解明、治療法探求のためのトランスレーショナル研究 (2019)
  • Author(s): 立石健祐, 佐々木重嘉, 河津正人, 三宅勇平, 中村大志, 吉井幸恵, 松下裕子, 山中正二, 山本哲哉, 脇本浩明, 永根基雄, 市村幸一
  • Organizer: 第37回日本脳腫瘍学会学術集会
• [Presentation] ヒト由来中枢神経原発悪性リンパ腫細胞株を用いた腫瘍発生進展機構の解明、治療法探求のためのトランスレーショナル研究 (2019)
  • Author(s): 立石健祐, 佐々木重嘉, 河津正人, 三宅勇平, 中村大志, 吉井幸恵, 松下裕子, 山中正二, 山本哲哉, 脇本浩明, 永根基雄, 市村幸一
  • Organizer: 20回日本分子脳神経外科学会
• [Presentation] Therapeutic development for malignant brain tumors: past and future perspectives (2018)
  • Author(s): Motoo Nagane
  • Organizer: The 36th Annual Meeting of the Japan Society of Brain Tumor Pathology
  • Invited
• [Presentation] Clinical trials for gliomas and primary central nervous system lymphoma in Japan by JCOG Brain Tumor Study Group (2018)
  • Author(s): Motoo Nagane
  • Organizer: The 15th Meeting of the Asian Society for Neuro-Oncology
  • Int'l Joint Research / Invited
• [Presentation] 中枢神経系原発悪性リンパに対するR-MPV-A療法の後方視的解析 (2018)
  • Author(s): 永根 基雄
  • Organizer: 第30回 多摩脳腫瘍研究会
• [Presentation] 中枢神経系原発悪性リンパ腫に対するR-MPV-A療法のHD-MTX単独療法に対する優越性 (2018)
  • Author(s): 永根 基雄
  • Organizer: 第36回 日本脳腫瘍学会学術集会
• [Presentation] 高齢者初発中枢神経系原発悪性リンパ腫に対する多剤併用免疫化学療法（R－MPV-A）の有用性 (2018)
  • Author(s): 永根 基雄
  • Organizer: 第32回日本老年脳神経外科学会
  • Invited
• [Presentation] Mutation of PIM1 gene in Primary Central Nervous System Lymphoma inhibits cell death through change in subcellular localization of Pim-1 and increase of BAD phosphorylation (2018)
  • Author(s): 佐々木重嘉、市村幸一、永根基雄、富山新太
  • Organizer: The 23rd Annual Scientific Meeting of the Society of Neuro-Oncology
  • Int'l Joint Research
• [Presentation] 中枢神経系悪性リンパ腫におけるPIM1遺伝子変異はPim-1細胞内局在の変化およびBADリン酸化の亢進を介して細胞死を抑制する (2018)
  • Author(s): 佐々木重嘉、市村幸一、永根基雄、富山新太
  • Organizer: 第36回 日本脳腫瘍学会学術集会
• [Presentation] 悪性脳腫瘍の治療開発：神経膠腫・悪性リンパ腫を主に (2018)
  • Author(s): 永根基雄
  • Organizer: 第10回三重脳腫瘍セミナー
  • Invited
• [Presentation] Efficacy and prognostic factors of combined immunochemotherapy R-MPV-A with reduced or deferred radiotherapy for patients with primary CNS lymphoma (2017)
  • Author(s): Motoo Nagane, Keiichi Kobayashi, Kuniaki Saito, Nobuyoshi Sasaki, Satoshi Kume, Yuki Yamagishi, Saki Shimizu, Kaori Suzuki, Yoshiaki Shiokawa
  • Organizer: 5th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies (WFNOS)
  • Int'l Joint Research
• [Presentation] Update on JCOG1114 for newly diagnosed PCNSL in Japan (2017)
  • Author(s): Motoo Nagane
  • Organizer: 2017 International PCNSL Collaborative Group Meeting
  • Int'l Joint Research
• [Presentation] Combined immunochemotherapy, R-MPV-A, with reduced or deferred radiotherapy for PCNSL improves survival with favorable performance and cognitive function (2016)
  • Author(s): Motoo Nagane, Keiichi Kobayashi, Kuniaki Saito, Nobuyoshi Sasaki, Satoshi Kume, Yuki Yamagishi, Saki Shimizu, Kaori Suzuki, Yoshiaki Shiokawa
  • Organizer: 21th Annual Meeting of the Society for Neuro-Oncology
  • Place of Presentation: Scottsdale, AZ, U.S.A.
  • Year and Date: 2016-11-18
  • Int'l Joint Research
• [Presentation] Genomic characterization of primary central nervous system lymphoma reveals predominant nonsynonymous somatic mutations of MYD88 and PIM1 genes (2016)
  • Author(s): Nagane M, Fukumura K, Ueno T, Lee J, Shishido-Hara Y, Mishima K, Ichimura K, Mukasa A, Narita Y, Aburatani H, Nishikawa R, Mano H
  • Organizer: 21th International Conference on Brain Tumor Research and Therapy
  • Place of Presentation: Okinawa, Japan
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Book] 脳腫瘍診療ガイドライン 改訂第2版（2019年版） (2019)
  • Author(s): 92.永根基雄
  • Total Pages: 199
  • Publisher: 金原出版
  • ISBN: 9784307203968
• [Book] 中枢神経系原発悪性リンパ腫．In 脳腫瘍診療ガイドライン 2016年版 (2016)
  • Author(s): 永根基雄：日本脳腫瘍学会（編）
  • Total Pages: 131
  • Publisher: 金原出版
• [Book] 悪性リンパ腫. In EBMに基づく脳神経疾患の基本治療指針 第4版 (2016)
  • Author(s): 永根基雄；田村晃，松谷雅生，清水輝夫，辻貞俊，塩川芳昭，成田善孝（編）
  • Total Pages: 807
  • Publisher: メジカルビュー社