Novel approaches to cancer treatment based on DNA damage and tumor immunity activation induced by proton beam irradiation

• Project/Area Number: 24390287
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• Research Institution: University of Tsukuba
• Principal Investigator: TSUBOI Koji 筑波大学, 医学医療系, 教授 (90188615)
• Co-Investigator(Kenkyū-buntansha): SAKAE Takeji 筑波大学, 医学医療系, 教授 (60162278) ; KUMADA Hiroaki 筑波大学, 医学医療系, 准教授 (30354913) ; MORITAKE Takashi 筑波大学, 医学医療系, 講師 (50450432) ; HASHIMOTO Takayuki 筑波大学, 医学医療系, 講師 (60400678) ; SUZUKI Kenshi 筑波大学, 医学医療系, 助教 (20726442)
• Co-Investigator(Renkei-kenkyūsha): ITO Atsuo 産業技術総合研究所, ヒューマンライフテクノロジー研究部門, グループリーダー (30356480) ; OHNO Tadao 日本歯科大学, 生命歯学部, 客員教授 (90160580)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000); Fiscal Year 2014: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2013: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2012: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: がん / 陽子線治療 / DNA損傷 / 化学療法 / 腫瘍免疫 / 粒子線治療 / 陽子線 / DNAクラスター損傷 / DNA塩基損傷 / DNA二本鎖切断

Outline of Final Research Achievements

1) The “complex DNA damages” induced by irradiation make a significant impact on cell inactivation or transformation. Although complex DNA damage formation was dependent on radiation quality in the early phase after irradiation, senescence-like growth arrest was suggested to be the major cellular response in the later phase, regardless of radiation quality.
2) A selective Cox-2 inhibitor “celecoxib” sensitized malignant brain tumor cells to gamma-rays by loading ER stress. The major modality of cell death induced was autophagy, suggesting that celecoxib is a promising candidate for radosensitizing refractory malignant brain tumors.
3) Local cancer radiotherapy may have an effect as an immune adjuvant. We found that a tumor-specific immune system was activated when the primary tumor was cured by irradiation. This “abscopal effect” was effective even in the brain. In contrast, primary tumor recurrence after irradiation resulted in suppression of tumor immunity.

Research Products

• [Journal Article] The Major DNA Repair Pathway after Both Proton and Carbon-Ion Radiation is NHEJ, but the HR Pathway is More Relevant in Carbon Ions. (2015)
  • Author(s): Gerelchuluun A, Manabe E, Ishikawa T, Sun L, Itoh K, Sakae T, Suzuki K, Hirayama R, Asaithamby A, Chen DJ, Tsuboi K.
  • Journal Title: Radiat Res. Volume: 183 Issue: 3 Pages: 345-356
  • DOI: 10.1667/rr13904.1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Long-term survival after treatment of glioblastoma multiforme with hyperfractionated concomitant boost proton beam therapy. (2015)
  • Author(s): Mizumoto M, Yamamoto T, Takano S, Ishikawa E, Matsumura A, Ishikawa H, Okumura T, Sakurai H, Miyatake S, Tsuboi K.
  • Journal Title: Pract Radiat Oncol. Volume: 5 Issue: 1 Pages: e9-e16
  • DOI: 10.1016/j.prro.2014.03.012
  • Peer Reviewed / Open Access
• [Journal Article] RBE and OER within the spread-out Bragg peak for proton beam therapy: in vitro study at the Proton Medical Research Center at the University of Tsukuba (2014)
  • Author(s): Kanemoto A, Hirayama R, Moritake T, Furusawa Y, Sun L, Sakae T, Kuno A, Terunuma T, Yasuoka K, Mori Y, Tsuboi K, Sakurai H.
  • Journal Title: J Radiat Res. Volume: 55 Issue: 5 Pages: 1028-1032
  • DOI: 10.1093/jrr/rru043
  • Peer Reviewed / Open Access
• [Journal Article] Homologous recombination pathway may play a major role in high-LET radiation-induced DNA double-strand break repair. (2014)
  • Author(s): Gerelchuluun A, Zhu J, Su F, Asaithamby A, Chen DJ, Tsuboi K.
  • Journal Title: Journal of Radiation Research Volume: 55 Issue: suppl 1 Pages: i83-i84
  • DOI: 10.1093/jrr/rrt181
  • Peer Reviewed
• [Journal Article] 陽子線・重粒子線治療 (2013)
  • Author(s): 坪井康次 水本斉志
  • Journal Title: Clinical Neuroscience Volume: 31 Pages: 1169-1172
• [Journal Article] A phase I study on combined therapy with proton-beam radiotherapy and in situ tumor vaccination for locally advanced recurrent hepatocellular carcinoma (2013)
  • Author(s): Abei M, Okumura T, Fukuda K, Hashimoto T, Araki M, Ishige K, Hyodo I, Kanemoto A, Numajiri H, Mizumoto M, Sakae T, Sakurai H, Zenkoh J, Ariungerel G, Sogo Y, Ito A,Ohno T, Tsuboi K
  • Journal Title: Radiat Oncol Volume: 16 Issue: 1 Pages: 239-239
  • DOI: 10.1186/1748-717x-8-239
  • Peer Reviewed
• [Journal Article] Reirradiation for recurrent malignant brain tumor with radiotherapy or proton beam therapy. Technical considerations based on experience at a single institution (2013)
  • Author(s): Mizumoto M, Okumura T, Ishikawa E, Yamamoto T, Takano S, Matsumura A, Oshiro Y, Ishikawa H, Sakurai H, Tsuboi K
  • Journal Title: Strahlenther Onkol Volume: 189 Issue: 8 Pages: 656-663
  • DOI: 10.1007/s00066-013-0390-6
  • Peer Reviewed
• [Journal Article] Celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress. (2013)
  • Author(s): Suzuki K, Gerelchuluun A, Hong Z, Sun L, Zenkoh J, Moritake T, Tsuboi K.
  • Journal Title: Neuro-Oncology Volume: 15 Issue: 9 Pages: 1186-1199
  • DOI: 10.1093/neuonc/not062
  • Peer Reviewed
• [Journal Article] Proton beam therapy for intracranial and skull base tumors. (2013)
  • Author(s): Mizumoto M, Oshiro Y, Tsuboi K.
  • Journal Title: Translational Cancer Research Volume: 2 Pages: 87-96
  • Peer Reviewed
• [Journal Article] In vitro stemness characterization of radioresistant clones isolated from a medulloblastoma cell line ONS-76 (2013)
  • Author(s): Sun L, Moritake T, Zheng YW, Suzuki K, Gerelchuluun A, Hong ZS, Zenkoh J, Taniguchi H, Tsuboi K
  • Journal Title: J Radiat Res Volume: 54(1) Issue: 1 Pages: 61-9
  • DOI: 10.1093/jrr/rrs078
  • NAID: 120007137110
  • Peer Reviewed
• [Journal Article] Lineal energy-based evaluation of oxidative DNA damage induced by proton beams and X-rays (2013)
  • Author(s): Zhengshan Hong, Yuki Kase, Takashi Moritake, Ariungerel Gerelchuluun, Lue Sun, Kenshi Suzuki, Toshiyuki Terunuma, Kiyoshi Yasuoka, Hiroaki Kumada, Kazunori Anzai, Hideyuki Sakurai, Takeji Sakae and Koji Tsuboi
  • Journal Title: Int. J. Radiat. Biol. Volume: Vol.89 Issue: 1 Pages: 36-43
  • DOI: 10.3109/09553002.2012.715791
  • Peer Reviewed
• [Journal Article] DNA-PK targeting virotherapy, a promising approach (2013)
  • Author(s): Tsuboi K
  • Journal Title: Transl Cancer Res Volume: 1 (1) Pages: 2-3
  • Peer Reviewed
• [Presentation] X線照射により発生する遅発性ROSが細胞の生存に与える影響の解析 (2014)
  • Author(s): 伊東一也、孫略、盛武敬、坪井康次
  • Organizer: 第29回日本酸化ストレス学会関東支部会
  • Place of Presentation: 筑波大学東京キャンパス（東京 文京区）
  • Year and Date: 2014-12-20
• [Presentation] ジクロロ酢酸ナトリウムによる癌幹細胞様クローンの放射線増感メカニズムの解明 (2014)
  • Author(s): 孫略、伊東一也、松本孔貴、盛武敬、坪井康次
  • Organizer: 第29回日本酸化ストレス学会関東支部会
  • Place of Presentation: 筑波大学東京キャンパス（東京 文京区）
  • Year and Date: 2014-12-20
• [Presentation] 放射線による細胞死研究の新展開 細胞死につながる初期過程を考察する (2014)
  • Author(s): 坪井康次、鈴木健之、Gerelchuluun Ariungerel
  • Organizer: 日本放射線影響学会 第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島）
  • Year and Date: 2014-10-01 – 2014-10-03
  • Invited
• [Presentation] 粒子線によるDNA二本鎖切断と修復機構 (2014)
  • Author(s): 真鍋絵梨, Ariungerel Gerelchuluun, 石川隆昭, 鈴木健之, Aroumougame Asaithamby, David J Chen , 坪井康次
  • Organizer: 日本放射線影響学会 第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] 休止期がん細胞内抗酸化物質が放射線抵抗性に及ぼす影響の解析 (2014)
  • Author(s): 伊東一也、孫略、石川隆昭、盛武敬、坪井康次
  • Organizer: 日本放射線影響学会 第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] 治療用陽子線と炭素線による 複雑なDNA損傷の評価 (2014)
  • Author(s): 石川隆昭、Ariungerel Gerelchuluun、伊東一也、孫 略、鈴木健之、真鍋絵梨、 Asaithamby Aroumagme、David J Chen、坪井康次
  • Organizer: 日本放射線影響学会 第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] エネルギー代謝機構が癌幹細胞性維持に及ぼす影響の解析 (2014)
  • Author(s): 孫略、伊東一也、松本孔貴、盛武敬、坪井康次
  • Organizer: 日本放射線影響学会 第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] Biological effectiveness of clinically used proton beam (2014)
  • Author(s): Ariungerel Gerelchuluun 、石川隆昭、真鍋絵梨、孫略、伊東和也、鈴木健之、善光純子、Aroumougame Asaithambi, David J Chen、坪井康次.
  • Organizer: 日本放射線影響学会 第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] DNA repair pathway after irradiation with clinically used charged particle beams (2014)
  • Author(s): Ariungerel Gerelchuluun, Takaaki Ishikawa, Eri Manabe, Lue Sun, Kazuya Ito, Kenshi Suzuki, Junko Zenkoh, Aroumougane Asaithambi, David J Chen, Koji Tsuboi.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 治療用陽子線と炭素線による 複雑なDNA損傷の形成と細胞応答 (2014)
  • Author(s): 石川隆昭、Ariungerel Gerelchuluun、伊東一也、孫 略、鈴木健之、真鍋絵梨、 Asaithamby Aroumagme、David J Chen、坪井康次
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Analysis of mitochondrial state in radioresistant cancer stem-like cells. (2014)
  • Author(s): Lue Sun, Takashi Moritake, Kazuya Ito, Kenshi Suzuki, Ariungerel Gerelchuluun, Zhengshan Hong and Koji Tsuboi.
  • Organizer: The 17th Biennial Meeting of Society for Free Radical Research International.
  • Place of Presentation: 京都国際会議場（京都府京都市）
• [Presentation] Biochemical properties of clinical High-Energy proton beams ; Comparison with x-ray and carbon ions. (2013)
  • Author(s): Koji Tsuboi
  • Organizer: 第3回国際放射線神経生物学会大会
  • Place of Presentation: 万国津梁館(沖縄)
  • Year and Date: 2013-01-26
• [Presentation] 治療用陽子線とエックス線によるclustered DNA damageの形成 (2013)
  • Author(s): 石川隆昭、ゲレルチュルン アリウンゲレル、洪正善、孫略、鈴木健之、善光純子、盛武敬、Aroumougame Asaithamby、David J. Chen、坪井康次
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] 脳腫瘍幹細胞様クローンのミトコンドリア活性が放射線抵抗性に及ぼす影響の解明 (2013)
  • Author(s): 孫略、伊東一也、鈴木健之、ゲレルチュルンアリウンゲレル、洪正善、盛武敬、坪井康次
  • Organizer: 日本放射線影響学会第56回大会
  • Place of Presentation: ホテルクラウンパレス青森（青森県青森市）
• [Presentation] 治療用陽子線とガンマ線によるDNA損傷修復メカニズムにおけるNHEJとHRの役割 (2013)
  • Author(s): ゲレルチュルン アリウンゲレル、石川隆昭、鈴木健之、洪正善、孫略、伊東一也、真鍋絵梨、善光純子、榮武二、盛武敬、Asaithamby A、David JC、坪井康次
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] Clinical Proton beam induced DNA damage and its repair mechanism (2013)
  • Author(s): ゲレルチュルン アリウンゲレル、石川隆昭、鈴木健之、洪正善、孫略、伊東一也、真鍋絵梨、善光純子、榮武二、盛武敬、Asaithamby A、David JC、坪井康次
  • Organizer: 日本放射線影響学会第56回大会
  • Place of Presentation: ホテルクラウンパレス青森（青森県青森市）
• [Presentation] Lineal energy-based evaluation of oxidative DNA damage induced by proton beams and X-rays (2013)
  • Author(s): Zhengshan Hong, Yuki Kase, Takashi Moritake, Ariungerel Gerelchuluun, Lue Sun, Kenshi Suzuki, Kazunori Anzai, Takeji Sakae, Koji Tsuboi
  • Organizer: 52nd Annual Conference of the Particle Therapy Co-Operative Group
  • Place of Presentation: エッセン ドイツ
• [Presentation] Clinical Proton beam induced DNA damage and its repair mechanism (2013)
  • Author(s): Gerelchuluun A, Manabe E, Ishikawa T, Suzuki K, Hong Z, Sun L, Ito K, Manabe E, Zenkoh J, Sakae T, Moritake T, Asaithamby A, David JC, Tsuboi K.
  • Organizer: 29th RBC-NIRS International Symposium
  • Place of Presentation: 京都大学（京都府京都市）
• [Presentation] Homologous Recombination Pathway play a Major role in High-LET Radiation Induced DNA Double-Strand Break Repair (2013)
  • Author(s): Gerelchuluun A, Zhu J, Su F, Asaithamby A, Chen DJ, Tsuboi K
  • Organizer: Heavy Ion in Therapy and Space Radiation Symposium 2013
  • Place of Presentation: The Keiyo Bank Culture Plaza, Chiba
• [Presentation] Skin reaction and antitumor effect induced by low energy x-ray micro beams. (2012)
  • Author(s): Zhengshan Hong
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: ロイトン札幌.さっぽろ芸文館.札幌市教育文化会館(札幌)
  • Year and Date: 2012-09-21
• [Presentation] Selective COX-2 inhibitor Celecoxib shows Radiosensitization by inducing ER stress. (2012)
  • Author(s): Kenshi Suzuki
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: ロイトン札幌.さっぽろ芸文館.札幌市教育文化会館(札幌)
  • Year and Date: 2012-09-20
• [Presentation] Identification of pancreatic cancer stem cell lineage during pancreatic tumorigenesis. (2012)
  • Author(s): Lue Sun
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: ロイトン札幌.さっぽろ芸文館.札幌市教育文化会館(札幌)
  • Year and Date: 2012-09-20
• [Presentation] Cell Inactivation Ability of High.Energy Proton Beams. (2012)
  • Author(s): Koji Tsuboi
  • Organizer: 15t^<th> International Congress on Neutron Capture Therapy.
  • Place of Presentation: つくば国際会議場(つくば市)(招待講演)
  • Year and Date: 2012-09-13
• [Presentation] Cell Inactivation Ability and Mechanism of Clinical High-Energy Proton Beams. (2012)
  • Author(s): Koji Tsuboi
  • Organizer: The 31st Sapporo International Cancer Symposium
  • Place of Presentation: 北海道大学医学部学友会館フラテ(札幌)
  • Year and Date: 2012-07-24
• [Presentation] Carbon vs. Proton for Innovative Applications of Particle Beam Therapy Do physical and biological differences between protons and carbon ions influence clinical results? (2012)
  • Author(s): Koji Tsuboi
  • Organizer: PTC0G51 Scientific Meeting
  • Place of Presentation: Coex, Seoul, Korea(招待講演)
  • Year and Date: 2012-05-17
• [Presentation] セレコキシブは、小胞体ストレスを負荷して低酸素下の膠芽腫細胞の放射線感受性を上げる
  • Author(s): 鈴木 健之、ゲレルチュルンアリウンゲレル、洪正善、孫略、盛武敬、坪井康次
  • Organizer: 第19回癌治療増感研究会
  • Place of Presentation: 東京医科歯科大学（東京都文京区）
• [Presentation] 癌幹細胞様クローンのミトコンドリア活性が癌幹細胞性維持に及ぼす影響の解析
  • Author(s): 孫略、伊東一也、鈴木健之、ゲレルチュルン アリウンゲレル、洪正善、盛武敬、坪井康次
  • Organizer: 第28回日本酸化ストレス学会関東支部例会
  • Place of Presentation: 日本薬科大学（埼玉県北足立郡）
• [Presentation] エックス線照射による腫瘍免疫応答的細胞死が脳内へ及ぼす影響
  • Author(s): Zenkoh J, Gerelchuluun A, Hong Z, Suzuki K, Sun L, Ito K, Miwa Y, Tsuboi K.
  • Organizer: The 4th Internarional Society of Radiation Neurobiology Conference
  • Place of Presentation: Takasaki Gunma