Integrated analyses of GBM cell lines, in vivo xenograft models, and clinical samples to examine the glutamine metabolism in response to mTOR-targeted treatments

• Project/Area Number: 26462181
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Kobe University
• Principal Investigator: TANAKA KAZUHIRO 神戸大学, 医学研究科, 医学研究員 (70467661)
• Co-Investigator(Kenkyū-buntansha): 篠山 隆司 神戸大学, 医学部附属病院, 講師 (10379399) ; 入野 康宏 神戸大学, 医学研究科, 特命助教 (10415565)
• Project Period (FY): 2014-04-01 – 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 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: グルタミン代謝 / グルタミナーゼ / mTOR / グリオーマ / ｍTOR

Outline of Final Research Achievements

The impact of mTOR inhibition on metabolic reprogramming in malignant glioma is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, in vivo models and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies reveal elevated glutaminase (GLS) and glutamate levels following mTOR kinase inhibitor treatment, which is confirmed in a xenograft model. GLS is shown to promote GBM survival following mTOR inhibitor treatment. Genetic and pharmacologic studies demonstrate that combined inhibition of mTOR kinase and GLS cause massive synergistic tumor cell death and growth inhibition in vivo. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance, and suggest a rational combination therapy to suppress it.

Research Products

• [Journal Article] Radiographic occult cerebellar germinoma presenting with progressive ataxia and cranial nerve palsy. (2016)
  • Author(s): Minami N, Tanaka K, Kimura H, Hirose T, Mori T, Maeyama M, Sekiya H, Uenaka T, Nakamizo S, Nagashima H, Mizukawa K, Itoh T, Sasayama T, Kohmura E.
  • Journal Title: BMC Neurol. Volume: 16 Issue: 1 Pages: 1-4
  • DOI: 10.1186/s12883-015-0516-9
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma (2016)
  • Author(s): 41.Nagashima H, Tanaka K, Sasayama T, Irino Y, Sato N, Takeuchi Y, Kyotani K, Mukasa A, Mizukawa K, Sakata J, Yamamoto Y, Hosoda K, Itoh T, Sasaki R, Kohmura E
  • Journal Title: Neuro Oncol. Volume: 18(11) Pages: 1559-1568
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Rapid tumor growth with glial differentiation of central neurocytoma after stereotactic radiosurgery (2016)
  • Author(s): 42.Tanaka H, Sasayama T, Yamashita H, Hara Y, Hayashi S, Yamamoto Y, Fujita Y, Okino T, Mizowaki T, Yamaguchi Y, Tanaka K, Kohmura E
  • Journal Title: J Clin Neurosci. Volume: 31 Pages: 188-92
  • DOI: 10.1016/j.jocn.2016.01.036
  • Peer Reviewed
• [Journal Article] [Association of Deep Venous Thrombosis with D-dimer Values in Patients with Hemorrhagic Stroke] (2016)
  • Author(s): 43.Arai A, Koyama J, Imahori T, Shiomi R, Iwahashi H, Tanaka K, Kohmura E
  • Journal Title: No Shinkei Geka. Volume: 44(12) Pages: 1019-1023
  • Peer Reviewed
• [Journal Article] Two Cases of Cerebral Infarction due to Focal Irradiation for Glioma in Adults (2015)
  • Author(s): Minami N, Mizukawa K, Iwahashi H, Nagashima H, Tanaka K, Sasayama T, Hosoda K, Mukumoto N, Sasaki R, Kohmura E.
  • Journal Title: Neurological Surgery 脳神経外科 Volume: 43 Issue: 4 Pages: 344-351
  • DOI: 10.11477/mf.1436203018
  • ISSN: 0301-2603, 1882-1251
  • Year and Date: 2015-04-10
  • Peer Reviewed
• [Journal Article] Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. (2015)
  • Author(s): Nakamura T, Tateishi K, Niwa T, Matsushita Y, Tamura K, Kinoshita M, Tanaka K, Fukushima S, Takami H, Arita H, Kubo A, Shuto T, Ohno M, Miyakita Y, Kocialkowski S, Sasayama T, Hashimoto N, Maehara T, Shibui S, Ushijima T, Kawahara N, Narita Y, Ichimura K.
  • Journal Title: Neuropathol Appl Neurobiol. Volume: 42(3) Issue: 3 Pages: 279-290
  • DOI: 10.1111/nan.12259
  • Peer Reviewed
• [Journal Article] Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment. (2015)
  • Author(s): Tanaka K, Sasayama T, Irino Y, Takata K, Nagashima H, Satoh N, Kyotani K, Mizowaki T, Imahori T, Ejima Y, Masui K, Gini B, Yang H, Hosoda K, Sasaki R, Mischel PS, Kohmura E.
  • Journal Title: J Clin Invest Volume: 125 Issue: 4 Pages: 1591-602
  • DOI: 10.1172/jci78239
  • Peer Reviewed / Open Access
• [Journal Article] STAT3 activation is associated with cerebrospinal fluid interleukin-10 (IL-10) in primary central nervous system diffuse large B cell lymphoma. (2015)
  • Author(s): Mizowaki T, Sasayama T, Tanaka K, Mizukawa K, Takata K, Nakamizo S, Tanaka H, Nagashima H, Nishihara M, Hirose T, Itoh T, Kohmura E
  • Journal Title: J Neurooncol Volume: 124(2) Issue: 2 Pages: 165-74
  • DOI: 10.1007/s11060-015-1843-9
  • Peer Reviewed
• [Journal Article] A 40-Year-Old Female with Leptomeningeal Lesions. (2015)
  • Author(s): Mizowaki T, Sasayama T, Semba S, Sasaki R, Yasuo K, Nakamizo S, Tanaka K, Mizukawa K, Uchihashi Y, Kohmura E.
  • Journal Title: Brain Pathol. Volume: 25 Issue: 4 Pages: 509-10
  • DOI: 10.1111/bpa.12270
  • Peer Reviewed / Open Access
• [Journal Article] Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance. (2015)
  • Author(s): Masui K, Tanaka K, Ikegami S, Villa GR, Yang H, Yong WH, Cloughesy TF, Yamagata K, Arai N, Cavenee WK, Mischel PS.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 112(30) Issue: 30 Pages: 9406-9411
  • DOI: 10.1073/pnas.1511759112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combined IDH1 mutation and MGMT methylation status on long-term survival of patients with cerebral low-grade glioma. (2015)
  • Author(s): Tanaka K, Sasayama T, Mizukawa K, Takata K, Sulaiman NS, Nishihara M, Kohta M, Sasaki R, Hirose T, Itoh T, Kohmura E.
  • Journal Title: Clin Neurol Neurosurg. Volume: 138 Pages: 37-44
  • DOI: 10.1016/j.clineuro.2015.07.019
  • Peer Reviewed / Open Access
• [Journal Article] Tumor-Associated Macrophages Associate with Cerebrospinal Fluid Interleukin-10 and Survival in Primary Central Nervous System Lymphoma (PCNSL) (2015)
  • Author(s): Sasayama T, Tanaka K, Mizowaki T, Nagashima H, Nakamizo S, Tanaka H, Nishihara M, Mizukawa K, Hirose T, Itoh T, Kohmura E
  • Journal Title: Brain Pathol. Volume: Aug 28 Issue: 4 Pages: 1-9
  • DOI: 10.1111/bpa.12318
  • Peer Reviewed
• [Journal Article] Targeting glutaminase and mTOR. (2015)
  • Author(s): Tanaka K, Sasayama T, Kohmura E.
  • Journal Title: Oncotarget. Volume: 6(29) Issue: 29 Pages: 26544-26545
  • DOI: 10.18632/oncotarget.5263
  • Peer Reviewed / Open Access
• [Journal Article] A large cavernous malformation of the third ventricle floor: A case report. (2015)
  • Author(s): Nagashima H, Tanaka K, Sasayama T, Okamura Y, Taniguchi M, Otani K, Yamasaki T, Itoh T, Kohmura E.
  • Journal Title: Neurol Neurochir Pol. Volume: 49(6) Issue: 6 Pages: 446-450
  • DOI: 10.1016/j.pjnns.2015.08.004
  • Peer Reviewed
• [Journal Article] 2.Different spatial distribution between germinal center B and non-germinal center B primary central nervous system lymphoma revealed by magnetic resonance group analysis. (2014)
  • Author(s): Kinoshita M1, Sasayama T, Narita Y, Yamashita F, Kawaguchi A, Chiba Y, Kagawa N, Tanaka K, Kohmura E, Arita H, Okita Y, Ohno M, Miyakita Y, Shibui S, Hashimoto N, Yoshimine T
  • Journal Title: Neuro Oncol Volume: 16 Issue: 5 Pages: 728-734
  • DOI: 10.1093/neuonc/not319
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Angiosarcoma arising in schwannoma of cerebellopontine angle and later associating with meningioma in a patient with neurofibromatosis type 2. (2014)
  • Author(s): Sakai Y, Hirose T, Tomono A, Kawakami F, Nakai T, Ohbayashi C, Mizowaki T, Tanaka K, Kohmura E, Itoh T.
  • Journal Title: Brain Tumor Pathol Volume: 31 Issue: 4 Pages: 293-8
  • DOI: 10.1007/s10014-014-0180-6
  • Peer Reviewed
• [Journal Article] Diagnostic yield and morbidity by neuronavigation-guided frameless stereotactic biopsy using magnetic resonance imaging and by frame-based computed tomography-guided stereotactic biopsy. (2014)
  • Author(s): Nishihara M, Takeda N, Harada T, Kidoguchi K, Tatsumi S, Tanaka K, Sasayama T, Kohmura E.
  • Journal Title: Surg Neurol Int Volume: 5 Issue: 9 Pages: 421-421
  • DOI: 10.4103/2152-7806.140211
  • Peer Reviewed / Open Access
• [Presentation] IDH遺伝子変異グリオーマのグルタミン代謝機構 (2016)
  • Author(s): 田中一寛、篠山隆司、長嶋宏明、佐藤直子、入野康宏、甲村英二
  • Organizer: 第34回日本脳腫瘍学会
  • Place of Presentation: 山梨
  • Year and Date: 2016-12-04
• [Presentation] Detection of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for diagnosing IDH1 mutant glioma (2016)
  • Author(s): Tanaka K, Nagashima H, Sasayama T, Satoh N, Irino Y, Kohmura E
  • Organizer: EANO 2016 meeting
  • Place of Presentation: Mannheim, GERMANY
  • Year and Date: 2016-10-12
  • Int'l Joint Research
• [Presentation] 悪性グリオーマのグルタミン代謝機構 (2016)
  • Author(s): 田中一寛、篠山隆司、長嶋宏明、佐藤直子、入野康宏、甲村英二
  • Organizer: 第75回日本脳神経外科学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-29
• [Presentation] Detection of IDH1 mutations in vivo by magnetic resonance spectroscopy of glutamate and 2-hydroxyglutarate in human brain gliomas (2016)
  • Author(s): Tanaka K, Nagashima H, Sasayama T, Satoh N, Irino Y, Kyotani K, Kohmura E
  • Organizer: The 21st International Conference on Brain Tumor Research and Therapy
  • Place of Presentation: Bankoku Shinryokan, Okinawa
  • Year and Date: 2016-04-10
  • Int'l Joint Research
• [Presentation] 悪性グリオーマのmTORシグナル阻害薬に対する代償的グルタミン代謝機構 (2015)
  • Author(s): 田中一寛、篠山隆司、入野康宏、佐藤直子、長嶋宏明、甲村英二
  • Organizer: 第33回日本脳腫瘍学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2015-12-06
• [Presentation] Increasing expression of glutaminase C (GAC) mRNA in malignant gliomas (2015)
  • Author(s): Kazuhiro Tanaka, Takashi Sasayama, Yasuhiro Irino, Hiroaki Nagashima, Naoko Satoh, Paul S. Mischel, and Eiji Kohmura
  • Organizer: 20th Annual Scientific Meeting and Education Day of the society for Neuro-Oncology
  • Place of Presentation: San Antonio, Texas、USA
  • Year and Date: 2015-11-19
  • Int'l Joint Research
• [Presentation] 悪性グリオーマのグルタミン代謝による代償的mTOR阻害薬耐性機構 (2015)
  • Author(s): 田中一寛、篠山隆司、入野康宏、佐藤直子、長嶋宏明、甲村英二
  • Organizer: 第74回日本脳神経外科学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2015-10-14
• [Presentation] 初発・再発時に覚醒下手術を2度行った優位半球言語野近傍グリオーマの1例 (2015)
  • Author(s): 田中一寛、篠山隆司、後藤田政子、長嶋宏明、山本祐輔、甲田将章、水川克、甲村英二
  • Organizer: 第13回 日本Awake surgery学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-09-24
• [Presentation] 悪性グリオーマのグルタミン代謝による代償的mTOR阻害薬耐性機構 (2015)
  • Author(s): 田中一寛、篠山隆司、入野康宏、佐藤直子、長嶋宏明、甲村英二
  • Organizer: 第3回がんと代謝研究会
  • Place of Presentation: 金沢
  • Year and Date: 2015-07-16
• [Presentation] A rapidly expanding immature teratoma originating from a neurohypophyseal germinoma (2015)
  • Author(s): Kazuhiro Tanaka, Masaaki Taniguchi, Masamitsu Nishihara, Takashi Sasayama, Yutaka Takahashi, and Eiji Kohmura
  • Organizer: The 4th International CNS Germ Cell Tumor Symposium
  • Place of Presentation: Tokyo
  • Year and Date: 2015-04-12
  • Int'l Joint Research
• [Presentation] ギリアデル留置後の脳浮腫および腫瘍摘出腔拡大と病理学的変化 (2014)
  • Author(s): 田中一寛、篠山隆司、長嶋宏明、水川克、伊藤智雄、甲村英二
  • Organizer: 第32回日本脳腫瘍学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 2014-11-30 – 2014-12-02
• [Presentation] Glutaminase-mediated metabolic pathway involves glioblastoma resistance to mTOR-targeted therapies (2014)
  • Author(s): Tanaka K, Sasayama T, Irino Y, Takata K, Nagashima H, Masui k, Gini B, Yang H, Mischel PS, and Kohmura E
  • Organizer: 19th Annual Scientific Meeting and Education Day of the society for Neuro-Oncology
  • Place of Presentation: Miami, Florida (USA)
  • Year and Date: 2014-11-13 – 2014-11-16
  • Invited
• [Presentation] Glutaminase-mediated metabolic pathway involves glioblastoma resistance to mTOR-targeted therapies (2014)
  • Author(s): Tanaka K, Sasayama T, Irino Y, Takata K, Nagashima H, Masui k, Gini B, Yang H, Mischel PS, and Kohmura E
  • Organizer: 19th World Congress on Advances in Oncology& 17th International Symposium on Molecular Medicine
  • Place of Presentation: Athens, Greece
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] Glutaminase-mediated metabolic pathway involves glioblastoma resistance to mTOR-targeted therapies (2014)
  • Author(s): Tanaka K, Sasayama T, Irino Y, Takata K, Nagashima H, Masui k, Gini B, Yang H, Mischel PS, and Kohmura E
  • Organizer: The 11th Meeting of Asian Society for Neuro-Oncology
  • Place of Presentation: Istanbul, Turkey
  • Year and Date: 2014-09-11 – 2014-09-14
• [Presentation] mTORシグナル阻害による悪性グリオーマ細胞内グルタミン代謝機構の変化 (2014)
  • Author(s): 田中一寛、篠山隆司、入野康宏、高田孔美、長嶋宏明、甲村英二
  • Organizer: 第2回がんと代謝研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] 早期に悪性転化を来したgranular cell astrocytoma の1例 (2014)
  • Author(s): 田中一寛、石井大嗣、水川克、篠山隆司、原重雄、平井千穂子、伊藤智雄、甲村英二
  • Organizer: 第32回日本脳腫瘍病理学会
  • Place of Presentation: 徳島
  • Year and Date: 2014-05-23 – 2014-05-24
• [Remarks] 脳腫瘍に関する研究
  • URL: http://www.med.kobe-u.ac.jp/neuro/research-tumor.html