Identification of new molecular target associated with treatment-resistance of glioblastomas

• Project/Area Number: 15K10349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: IUCHI TOSHIHIKO 千葉県がんセンター(研究所), 脳神経外科, 部長 (80370881)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: glioblastoma / radiation / chemotherapy / resistance / molecular target / DNA repair / 神経膠芽腫 / 放射線治療 / 化学療法 / 遺伝子発現 / 治療抵抗性 / 分子標的 / テモゾロミド / IMRT / CTOS / MGMT / 1p/19q今日欠失 / IDH / 1p/19q共欠失

Outline of Final Research Achievements

Copy number decrease of Rad51 (an essential factor of homologous recombination:HR) and XRCC6 (coding Ku70 which acts as the cornerstone of the non-homologous end joining: NHEJ) were associated with the survival of patients after chemo-radiotherapy, and were suspected to be a key molecule of tumor resistance to the treatment. However, from the comparative study of gene expression profiles between the samples from tumors pre- and just post-chemo-radiotherapy, genes involved in HR and NHEJ were down-regulated by the treatment, while CDKN1A and DDB2 expressions were up-regulated in the all cases. These data suggested the significant role of cell cycle arrest by CDKN1A and nucleotide excision repair, not HR nor NHEJ, plays a major role in tumor resistance to chemo-radiotherapy in glioblastomas.

Research Products

• [Journal Article] Clinical significance of the 2016 WHO classification in Japanese patients with gliomas. (2018)
  • Author(s): Iuchi T, Sugiyama T, Ohira M, et al.
  • Journal Title: Brain Tumor Pathol. Volume: 35 Issue: 2 Pages: 71-80
  • DOI: 10.1007/s10014-018-0309-0
  • Peer Reviewed
• [Journal Article] EGFR変異陽性非小細胞肺癌由来転移性脳腫瘍治療におけるチロシンキナーゼ阻害剤と定位照射. (2018)
  • Author(s): 井内俊彦, 新行内雅人, 永野修, 瀬戸口大樹, 長谷川祐三, 堺田司.
  • Journal Title: 定位的放射線治療 Volume: 22 Pages: 97-104
  • Peer Reviewed
• [Journal Article] Diagnostic Performance and Safety of Positron Emission Tomography Using 18F-Fluciclovine in Patients with Clinically Suspected High- or Low-grade Gliomas: A Multicenter Phase IIb Trial. (2017)
  • Author(s): Wakabayashi T, Iuchi T, Tsuyuguchi N, et al.
  • Journal Title: Asia Ocean J Nucl Med Biol Volume: 5 Pages: 10-21
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas (2017)
  • Author(s): Fukushima S, Yamashita S, Kobayashi H, et al.; Intracranial Germ Cell Tumor Genome Analysis Consortium (The iGCTConsortium).
  • Journal Title: Acta Neuropathologica Volume: 133 Issue: 3 Pages: 445-462
  • DOI: 10.1007/s00401-017-1673-2
  • Peer Reviewed / Open Access
• [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] The influence of carmustine wafer implantation on tumor bed cysts and peritumoral brain edema. (2016)
  • Author(s): Hasegawa Y, Iuchi T, Sakaida T, Yokoi S, Kawasaki K.
  • Journal Title: J Clin Neurosci Volume: 31 Pages: 67-71
  • DOI: 10.1016/j.jocn.2015.12.033
  • Peer Reviewed
• [Journal Article] A prospective, multicentre, single-arm clinical trial of bevacizumab for patients with surgically untreatable, symptomatic brain radiation necrosis. (2016)
  • Author(s): Furuse M, Nonoguchi N, Kuroiwa T, Miyamoto S, Arakawa Y, Shinoda J, Miwa K, Iuchi T, Tsuboi K, Houkin K, Terasaka S, Tabei Y, Nakamura H, Nagane M, Sugiyama K, Terasaki M, Abe T, Narita Y, Saito N, Mukasa A, Ogasawara K, Beppu T, Kumabe T, Nariai T, Tsuyuguchi N, Nakatani E, Kurisu S, Nakagawa Y, Miyatake SI.
  • Journal Title: Neurooncol Pract. Volume: 3 Pages: 272-280
  • Peer Reviewed
• [Journal Article] Levetiracetam versus phenytoin for seizure prophylaxis during and early after craniotomy for brain tumours: a phase II prospective, randomised study. (2015)
  • Author(s): Iuchi T, Kuwabara K, Matsumoto M, Kawasaki K, Hasegawa Y, Sakaida T.
  • Journal Title: J Neurol Neurosurg Psychiatry. Volume: 未定 Issue: 10 Pages: 1158-1162
  • DOI: 10.1136/jnnp-2014-308584
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Frequency of brain metastases in non-small-cell lung cancer and their association with epidermal growth factor receptor mutations. (2015)
  • Author(s): Toshihiko Iuchi, Masato Syngyoji, Meiji Itakura, Sana Yokoi, Yasumitsu Moriya, Hajime Tamura, Yasushi Yoshida, Hironori Ashinuma, Koichiro Kawasaki, Yuzo Hasegawa, Tsukasa Sakaida.
  • Journal Title: Int J Clin Oncol Volume: 20 Issue: 4 Pages: 674-679
  • DOI: 10.1007/s10147-014-0760-9
  • Peer Reviewed
• [Journal Article] Methionine uptake and the required radiation dose to control glioblastoma. (2015)
  • Author(s): Toshihiko Iuchi, Kazuo Hatano, Yoshio Uchino, Makiko Itami, Yuzo Hasegawa, Koichiro Kawasaki, Tsukasa Sakaida, Ryusuke Hara
  • Journal Title: Int J Radiat Oncol Biol Phys Volume: 93 Issue: 1 Pages: 133-140
  • DOI: 10.1016/j.ijrobp.2015.04.044
  • Peer Reviewed
• [Journal Article] Human Chorionic Gonadotropin is Expressed Virtually in All Intracranial Germ Cell Tumors. (2015)
  • Author(s): Takami H, Fukushima S, Fukuoka K, Suzuki T, Yanagisawa T, Matsushita Y, Nakamura T, Arita H, Mukasa A, Saito N, Kanamori M, Kumabe T, Tominaga T, Kobayashi K, Nagane M, Iuchi T, et al.
  • Journal Title: J Neurooncol Volume: 124 Issue: 1 Pages: 23-32
  • DOI: 10.1007/s11060-015-1809-y
  • Peer Reviewed
• [Presentation] Leptomeningeal carcinomatosis from EGFR-mutated non-small cell lung cancer. (2017)
  • Author(s): Toshihiko Iuchi, Masato Shingyoji, Taiki Setoguchi, Yasushi Yoshida, Hironori Ashinuma, Yuzo Hasegawa, Tsukasa Sakaida.
  • Organizer: ESMO(European society for Medical Oncology) 2017 Congress.
  • Int'l Joint Research
• [Presentation] Tailor-made setting of radiation doses owing to the MGMT gene promoter methylation for the treatment of IDH-wildtype primary glioblastoma. (2017)
  • Author(s): Toshihiko Iuchi, Kazuo Hatano, Ryusuke Hara, Makoto Saito, Daiki Setoguchi, Shiro Ikegami, Yuzo Hasegawa.
  • Organizer: ASTRO(American Society for Radiation Oncology) 2017 Annual Meeting.
  • Int'l Joint Research
• [Presentation] Tailor-made setting of radiation doses owing to the MGMT gene promoter methylation for the treatment of IDH-wildtype primary glioblastoma. (2017)
  • Author(s): Toshihiko Iuchi1, Kazuo Hatano3, Ryusuke Hara2, Makoto Saito2, Daiki Setoguchi1, Yuzo Hasegawa1, Tsukasa Sakaida.
  • Organizer: The 14th Meeting of the Asian Society for Neuro-Oncology.
  • Int'l Joint Research
• [Presentation] Clinical Significance of new WHO classification of gliomas. (2017)
  • Author(s): T. Iuchi, T. Sugiyama, S. Yokoi, M. Itami, D. Setoguchi, S. Ikegami, Y. Hasegawa.
  • Organizer: 第35回日本脳腫瘍病理学会
• [Presentation] IDH野生型初発神経膠芽腫治療に対する放射線治療 ~MGMTメチル化に基づく個別化線量設定~ (2017)
  • Author(s): 井内 俊彦, 幡野 和男, 原 竜介, 斉藤 真, 瀬戸口 大毅, 長谷川 祐三, 堺田 司
  • Organizer: 日本脳神経外科学会第76回学術総会
• [Presentation] 神経膠腫におけるてんかん発症の診断的価値 (2017)
  • Author(s): 井内俊彦, 瀬戸口大毅, 長谷川祐三, 堺田司
  • Organizer: 第35回日本脳腫瘍学会学術集会
• [Presentation] Tyrosine kinase inhibitors alone as a first-line treatment for patients with non-small-cell lung cancer harboring mutant epidermal growth factor receptor (2016)
  • Author(s): T. Iuchi, M. Shingyoji M. Itakura, Y. Hasegawa, Y. Yoshida, S. Ikegami, T. Setoguchi, H. Ashinuma
  • Organizer: ESMO (European Society of Medical Oncology) 2016 Congress
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2016-10-07
  • Int'l Joint Research
• [Presentation] 神経膠芽腫に対するベバシズマブの生命予後改善効果～通常照射と寡分割大線量IMRT症例における効果の違い～ (2016)
  • Author(s): 井内 俊彦, 瀬戸口大毅, 池上史郎, 長谷川祐三
  • Organizer: 日本脳神経外科学会第75回学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-28
• [Presentation] 神経膠腫の放射線抵抗性に係わる候補遺伝子～ゲノムコピー数変化および遺伝子発現と予後との相関から～ (2016)
  • Author(s): 池上史郎, 長谷川祐三, 瀬戸口大毅, 大平美紀, 井内俊彦
  • Organizer: 日本脳神経外科学会第75回学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-28
• [Presentation] 神経膠腫疑い患者に対するPET新規アミノ酸トレーサー 18F-fluciclovine の有効性及び安全性：多施設共同前向き臨床試験 (2016)
  • Author(s): 若林俊彦, 井内俊彦, 露口尚弘, 西川亮, 荒川芳輝, 篠山隆司, 三宅啓介, 成相直, 成田善孝, 橋本直哉, 屋田修, 松田博史, 窪田和雄, 伊藤公輝, 中里洋一, 久保村幹細
  • Organizer: 日本脳神経外科学会第75回学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-28
• [Presentation] 高線量放射線治療併用BCNUウエハー留置単群試験 長期臨床成績と晩期合併症 (2016)
  • Author(s): 長谷川祐三, 井内 俊彦, 瀬戸口大毅, 池上史郎
  • Organizer: 日本脳神経外科学会第75回学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-28
• [Presentation] Changes in apparent diffusion coefficient by bevacizumab as a prognostic factor of patients with progressed GBMs after irradiation - a comparative study with methionine-uptake on PET-. (2016)
  • Author(s): T. Iuchi, T. Sakaida, K. Hatano, M. Saito, Y. Hasegawa, S. Hirono, D. Ito, R.Hara
  • Organizer: ASTRO (American Society of Therapeutic Radiation Oncology) 2016 58th Annual Meeting
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-09-25
  • Int'l Joint Research
• [Presentation] Changes in apparent diffusion coefficient by bevacizumab as a prognostic factor of patients with progressed GBMs after irradiation - a comparative study with methionine-uptake on PET- (2016)
  • Author(s): T. Iuchi, T. Sakaida, K. Hatano, M. Saito, Y. Hasegawa, S. Hirono, D. Ito, R. Hara
  • Organizer: ASTRO 2016 58th Annual Meeting
  • Place of Presentation: Boston
  • Year and Date: 2016-09-25
  • Int'l Joint Research
• [Presentation] Hypofractionated IMRT for GBMs ~ Tailor-made setting of treatment doses owing to MGMT-methylation status~ (2016)
  • Author(s): Toshihiko Iuchi, Kazuo Hatano, Ryusuke Hara, Sana Yokoi, Daisuke Ito, Siichiro Hirono, Yuzo Hasegawa, Tsukasa Sakaida.
  • Organizer: The 21st International Conference on Brain Tumor Research and Therapy.
  • Place of Presentation: Okinawa, Japan
  • Year and Date: 2016-04-10
  • Int'l Joint Research
• [Presentation] Hypo-fractionated IMRT with TMZ for GBMs -Tailor-made setting of treatment doses owing to MGMT-methylation status- (2016)
  • Author(s): Toshihiko Iuchi, Kazuo Hatano, Ryusuke Hara, Sana Yokoi, Daisuke Ito, Seiishiro Hirono, Yuzo Hasegawa, Tsukasa Sakaida
  • Organizer: 21st. International Conference on Brain Tumor Research and Therapy
  • Place of Presentation: Okinawa
  • Year and Date: 2016-04-10
  • Int'l Joint Research
• [Presentation] Chromosomal aberrations and expression levels of genes involved in DNA damage repair and their associations with survival of patients with glioblastoma after irradiation (2015)
  • Author(s): T. Iuchi, M. Ohira, K. Hatano, M. Itami, M. Saito, T. Sakaida, Y. Hasegawa, S. Hirono, R. Hara
  • Organizer: ASTRO 2015 57th Annual Meeting
  • Place of Presentation: San Antonio
  • Year and Date: 2015-10-18
  • Int'l Joint Research
• [Presentation] MGMT非メチル化神経膠芽腫の局所制御に対する大線量照射とテモゾロ ミドの相乗効果 (2015)
  • Author(s): 井内 俊彦, 原 竜介, 横井 左奈, 長谷川 祐三, 廣野 誠一郎, 伊東 大祐, 堺田 司
  • Organizer: 日本脳神経外科学会第74回学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2015-10-14
• [Presentation] Synergic effect of high-dose irradiation and temozolomide on local control of MGMT unmethylated glioblastomas (2015)
  • Author(s): Toshihiko Iuchi, Ryusuke Hara, Kazuo Hatano, Sana Yokoi, Makiko Itami, Seiichiro Hirono, Yuzo Hasegawa, Tsukasa Sakaida
  • Organizer: European Cancer Congress
  • Place of Presentation: Vienna
  • Year and Date: 2015-09-25
  • Int'l Joint Research
• [Book] 脳腫瘍臨床病理カラーアトラス 第4版 (2017)
  • Author(s): 日本脳腫瘍病理学会（分担執筆）
  • Total Pages: 231
  • Publisher: 医学書院
  • ISBN: 9784260030472