Novel strategy to enhance temozolomide sensitivity with interference of base excision DNA repair system for malignant glioma

• Project/Area Number: 25462277
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Kyorin University
• Principal Investigator: Nagane Motoo 杏林大学, 医学部, 教授 (60327468)
• Research Collaborator: SHIOKAWA Yoshiaki ; OKADA Kyoko ; SHIMIZU Saki ; SUZUKI Kaori ; McDONALD Kerrie
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 脳腫瘍 / 神経膠腫 / PARP阻害剤 / テモゾロミド耐性 / 膠芽腫 / temozolomide / 薬剤耐性 / MGMT / ABT888 / temozolomide耐性

Outline of Final Research Achievements

Glioblastoma (GBM) is highly malignant and intractable to standard temozolomide (TMZ) treatment. TMZ induces cytotoxic O6-methylguanine lesion in tumor cell DNA, which is repaired by MGMT leading to TMZ resistance. TMZ preferentially induces N7-methylguanine and N3-methylalanine lesions, but they can be repaired through base excision repair system where poly (ADP-ribose) polymerase (PARP) plays a central role. Thus interference with PARP would be expected to conquer TMZ resistance. We treated human GBM cell lines with PARP inhibitors (ABT888) with or without TMZ and found that combination of TMZ plus ABT888 significantly strengthened cell death in GBM cell lines with methylated MGMT but also in those with unmethylated MGMT compared to either treatment alone. This synergistic effect was further observed in GBM cell lines derived from TMZ refractory patients as well as TMZ-resistant subclones. These results suggest the potential clinical usefulness of combining PARP inhibitors to TMZ.

Research Products

• [Journal Article] Genetic and epigenetic stability of oligodendrogliomas at recurrence. (2017)
  • Author(s): Aihara K, Mukasa A, Nagae G, Nomura M, Yamamoto S, Ueda H, Tatsuno K, Shibahara J, Takahashi M, Momose T, Tanaka S, Takayanagi S, Yanagisawa S, Nejo T, Takahashi S, Omata M, Otani R, Saito K, Narita Y, Nagane M, Nishikawa R, Ueki K, Aburatani H, Saito N
  • Journal Title: Acta Neuropathol Commun. Volume: 5 Issue: 1 Pages: 18-18
  • DOI: 10.1186/s40478-017-0422-z
  • Peer Reviewed / Open Access
• [Journal Article] 高齢者膠芽腫に対する術後放射線治療および化学療法の選択と予後に関する検討 (2017)
  • Author(s): 山岸 夢希, 小林 啓一, 齊藤 邦昭, 久米 賢, 川井田 善太郎, 佐々木 重嘉, 塩川 芳昭, 永根 基雄
  • Journal Title: Geriatric Neurosurgery Volume: 29 Pages: 25-37
  • NAID: 40021684402
• [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] A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas (2016)
  • Author(s): Arita H, Yamasaki K, Matsushita Y, Nakamura T, Shimokawa A, Takami H, Tanaka S, Mukasa A, Shirahata M, Shimizu S, Suzuki K, Saito K, Kobayashi K, Higuchi F, Uzuka T, Otani R, Tamura K, Sumita K, Ohno M, Miyakita Y, Kagawa N, Hashimoto N, Hatae R, Yoshimoto K, Shinojima N, Nakamura H, Kanemura Y, Okita Y, et al.
  • Journal Title: Acta Neuropathol Commun. Volume: 4 Issue: 1 Pages: 79
  • DOI: 10.1186/s40478-016-0351-2
  • Peer Reviewed / Open Access
• [Journal Article] 神経膠腫における 1H-Magnetic Resonance Spectroscopy (MRS)とLCModelを用いた2-hydroxyglutarate (2-HG)検出及びその定量的解析 (2016)
  • Author(s): 久米賢, 五明美穂, 小林啓一, 齊藤邦昭, 土屋一洋, 似鳥俊明, 塩川芳昭, 永根基雄
  • Journal Title: 杏林医会誌 Volume: 47
• [Journal Article] The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-) (2016)
  • Author(s): Tsuchihashi K, Okazaki S, Ohmura M, Ishikawa M, Sampetrean O, Onishi N, Wakimoto H, Yoshikawa M, Seishima R, Iwasaki Y, Morikawa T, Abe S, Takao A, Shimizu M, Masuko T, Nagane M, Furnari FB, Akiyama T, Suematsu M, Baba E, Akashi K, Saya H, Nagano O.
  • Journal Title: Cancer Research Volume: in press Issue: 10 Pages: 2954-2963
  • DOI: 10.1158/0008-5472.can-15-2121
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nimotuzumab enhances temozolomide induced growth suppression of glioma cells expressing mutant EGFR in vivo (2016)
  • Author(s): Nitta Y, Shimizu S, Shishido-Hara Y, Suzuki K, Shiokawa Y, Nagane M
  • Journal Title: Cancer Med Volume: 5 Issue: 3 Pages: 486-499
  • DOI: 10.1002/cam4.614
  • Peer Reviewed
• [Journal Article] 再発膠芽腫に対する治療のup to date (2016)
  • Author(s): 小林啓一，永根基雄
  • Journal Title: 脳神経外科速報 Volume: 26 Pages: 939-947
• [Journal Article] 脳腫瘍に対するimmune checkpoint阻害薬の開発状況 (2016)
  • Author(s): 永根基雄
  • Journal Title: 腫瘍内科 Volume: 17 Pages: 20-27
• [Journal Article] Astrocytic tumors（星細胞腫系腫瘍）―脳腫瘍Update (2016)
  • Author(s): 永根基雄
  • Journal Title: 脳神経外科 Volume: 44 Pages: 71-89
• [Journal Article] Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy (2016)
  • Author(s): Ichimura K, Fukushima S, Nagane M, The Intracranial Berm Cell Tumor Genome Analysis Consortium, et al
  • Journal Title: Acta Neuropathol Volume: Published online: 08 March Issue: 6 Pages: 889-901
  • DOI: 10.1007/s00401-016-1557-x
  • Peer Reviewed
• [Journal Article] 星細胞腫系神経膠腫の標準治療 (2015)
  • Author(s): 永根基雄
  • Journal Title: Neuro-Oncologyの進歩 Volume: 22 (3) Pages: 8-20
  • NAID: 130005117930
  • Peer Reviewed
• [Journal Article] C viral inclusions in progressive multifocal leukoencephalopathy: Scaffolding promyelocytic leukemia nuclear bodies grow with cell cycle transition through an S-to-G2-like state in enlarging oligodendrocyte nuclei (2014)
  • Author(s): Shishido-Hara Y, Yazawa T, Nagane M, Higuchi K, Abe-Suzuki S, Kurata M, Kitagawa M, Kamma H, Uchihara T
  • Journal Title: J Neuropathol Exp Neurol Volume: 73 Issue: 5 Pages: 442-453
  • DOI: 10.1097/nen.0000000000000066
  • Peer Reviewed / Open Access
• [Journal Article] 再発膠芽腫 (2014)
  • Author(s): 永根基雄
  • Journal Title: 脳21 Volume: 17 Pages: 20-28
• [Journal Article] Identification of distinct subgroup of glioma and novel genes related to malignant progression by genome-wide methylation analysis (2013)
  • Author(s): Saito K, Mukasa A, Nagae G, Nagane M, Aihara K, Takayanagi S, Tanaka S, Aburatani H, Saito N
  • Journal Title: Neuro-Oncology Volume: 15 Supplement 3
  • Peer Reviewed
• [Journal Article] Combining PARP inhibitors with TMZ: Improved efficacy observed in recurrent patient-derived cell lines compared to primary cells (2013)
  • Author(s): Nozue-Okada K, Nagane M, McDonald KL
  • Journal Title: Neuro-Oncology Volume: 15 Supplement 3
  • Peer Reviewed
• [Journal Article] Combination treatment with the anti-EGFR monoclonal antibody, nimotuzumab, and temozolomide causes synergistic growth suppression of mutant EGFR expressing glioma xenografts (2013)
  • Author(s): Nagane M, Nitta Y, Shimizu S, Shishido-Hara Y, Shiokawa Y
  • Journal Title: Proceedings of 104th Annual Meeting of the American Association for Cancer Research Volume: 54
  • Peer Reviewed
• [Journal Article] Predictive value of mean apparent diffusion coefficient value for responsiveness of temozolomide-refractory malignant glioma to bevacizumab. (2013)
  • Author(s): Nagane M, et al.
  • Journal Title: Int J Clin Oncol Volume: 19 Issue: 1 Pages: 16-23
  • DOI: 10.1007/s10147-013-0517-x
  • Peer Reviewed
• [Journal Article] evacizumab for glioblastoma – a promising drug or not? (2013)
  • Author(s): Nagane M, Nishikawa R
  • Journal Title: Cancers Volume: 5 Issue: 4 Pages: 1456-1468
  • DOI: 10.3390/cancers5041456
  • Peer Reviewed
• [Presentation] WHO2016 updateに伴う退形成性神経膠腫の診断・治療上の問題点 (2017)
  • Author(s): 永根基雄、小林啓一、齊藤邦昭、清水早紀、鈴木香、千葉知宏、柴原純二、塩川芳昭
  • Organizer: 第52回 ニューロオンコロジイの会
  • Place of Presentation: 新宿、東京
  • Year and Date: 2017-01-14
• [Presentation] Tolerability and pharmacokinetics (PK) of ABT-414 in Japanese patients (pts) with malignant glioma (2016)
  • Author(s): Nagane M, Narita Y, Kagawa N, Mishima K, Yamamoto T, Wakabayashi T, Hamada T, Odagawa R, Nishimura Y, Kiriyama T, Xiong H, Ocampo C, Nishikawa R
  • Organizer: ESMO ASIA 2016
  • Place of Presentation: Singapore
  • Year and Date: 2016-12-17
  • Int'l Joint Research
• [Presentation] Difficult Anaplastic Glioma (2016)
  • Author(s): Motoo Nagane
  • Organizer: ESMO ASIA 2016
  • Place of Presentation: Singapore
  • Year and Date: 2016-12-16
  • Int'l Joint Research / Invited
• [Presentation] 悪性神経膠腫に関する国内外の臨床研究動向 (2016)
  • Author(s): 永根基雄
  • Organizer: GLIADEL CONFERENCE IN TOKYO
  • Place of Presentation: 新宿
  • Year and Date: 2016-12-10
  • Invited
• [Presentation] 悪性脳腫瘍治療のエビデンスと標準治療：神経膠腫・悪性リンパ腫を中心に (2016)
  • Author(s): 永根基雄
  • Organizer: 第7回悪性神経膠腫治療カンファレンス
  • Place of Presentation: 京都市
  • Year and Date: 2016-10-21
  • Invited
• [Presentation] Integrated analysis of methylation of MGMT promoter and alteration of mismatch repair enzymes in glioblastoma (2016)
  • Author(s): Nagane M, Saito K, Kobayashi K, Shimizu S, Suzuki K, Sasaki N, Kume S, Yamagishi Y, Shiokawa Y
  • Organizer: 13th Asian Society for Neuro-Oncology Annual Scientific Meeting
  • Place of Presentation: Sidney, Australia
  • Year and Date: 2016-09-11
  • Int'l Joint Research
• [Presentation] 神経膠腫の標準治療とWHO2016新分類下での治療開発 (2016)
  • Author(s): 永根基雄
  • Organizer: 第21回日本脳腫瘍の外科学会
  • Place of Presentation: 港区，東京都
  • Year and Date: 2016-09-09
  • Invited
• [Presentation] 悪性脳腫瘍治療最新事情～2016年ASCO報告解説～ (2016)
  • Author(s): 永根基雄
  • Organizer: 脳腫瘍2016
  • Place of Presentation: 大阪市
  • Year and Date: 2016-07-22
  • Invited
• [Presentation] 悪性神経膠腫の標準治療と分子病理分類：Update (2016)
  • Author(s): 永根基雄
  • Organizer: 静岡県総合画像診断研究会総会 平成28年特別講演会
  • Place of Presentation: 静岡市
  • Year and Date: 2016-01-09
  • Invited
• [Presentation] 再発膠芽腫に対する用量強化テモゾロミド-ベバシズマブ逐次併用療法：新規多施設共同ランダム化第III相試験JCOG1308 (2015)
  • Author(s): 永根基雄、小林啓一、水澤純基、片山宏、成田善孝、田部井勇助、齊藤邦昭、福田治彦、西川亮、JCOG脳腫瘍グループ
  • Organizer: 第74回日本脳神経外科学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 2015-10-15
• [Presentation] 再発悪性神経膠腫に対するベバシズマブ併用ACNU療法（BEVAC療法） (2015)
  • Author(s): 永根基雄、小林啓一、齊藤邦昭、久米賢、川井田善太郎、清水早紀、鈴木香、塩川芳昭
  • Organizer: 第49回ニューロオンコロジイの会
  • Place of Presentation: 新宿区，東京都
  • Year and Date: 2015-08-09
• [Presentation] Chemotherapy for treatment of high-grade glioma: Any roles to potentiate stereotactic radiotherapy? (2015)
  • Author(s): Motoo Nagane
  • Organizer: 12th International Stereotactic Radiosurgery Society Congress
  • Place of Presentation: Yokohama
  • Year and Date: 2015-06-08
  • Int'l Joint Research / Invited
• [Presentation] Combining PARP inhibitors with TMZ improved efficacy observed in recurrent patient-derived cell lines compared to primary cells
  • Author(s): Nozue-Okada K, Ha W, Nagane M, Khasraw M, McDonald KL
  • Organizer: 2013 The 4th Quadrennial Meeting of the World Federation of Neuro-Oncology /The18th Annual Meeting of the Society for Neuro-Oncology.
  • Place of Presentation: San Francisco, CA, U.S.A.
• [Book] 10q LOH．In 脳腫瘍学 ―基礎研究と臨床研究の進歩－. II. 脳腫瘍の分子生物学と発生機序． (2016)
  • Author(s): 齊藤邦昭，永根基雄
  • Publisher: 日本臨牀
• [Book] 星細胞腫系腫瘍. in 脳神経外科学II [改訂12版] (2016)
  • Author(s): 永根基雄
  • Publisher: 金芳堂
• [Book] 星細胞腫系腫瘍. in 脳神経外科学II [改訂12版] (2016)
  • Author(s): 永根基雄、他
  • Total Pages: 2960
  • Publisher: 金芳堂