Effective combination of heavy ion beams and anti-VEGF antibody by targeting neural tumor stem cells

• Project/Area Number: 15H04909
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Radiation science
• Research Institution: Nara Medical University
• Principal Investigator: Hasegawa Masatoshi 奈良県立医科大学, 医学部, 教授 (50251111)
• Co-Investigator(Kenkyū-buntansha): 下田 絵美子 奈良県立医科大学, 医学部附属病院, 研究員 (00596950) ; 大野 達也 群馬大学, 重粒子線医学推進機構, 教授 (10344061) ; 若月 優 自治医科大学, 医学部, 教授 (40399449) ; 若井 展英 奈良県立医科大学, 医学部, 助教 (50745338) ; 八巻 香織 奈良県立医科大学, 医学部附属病院, 研究員 (50789881) ; 三浦 幸子 奈良県立医科大学, 医学部, 講師 (60597095) ; 井上 和也 奈良県立医科大学, 医学部附属病院, 研究員 (20596952)
• Research Collaborator: Mori Eiichiro
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2017: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2015: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 神経系腫瘍 / 幹細胞 / CD133 / Nestin / 抗VEGF抗体 / 重粒子線 / 腫瘍血管 / 炭素イオン線 / 悪性神経膠腫 / アポトーシス / p53 / 血管 / VEGF / 放射線

Outline of Final Research Achievements

To evaluate the efficacy of the combination of X-ray or high-LET carbon ion beams and anti-VEGF antibody for high grade neural or glial tumors, in vitro and in vivo studies were performed. In vitro study: VEGF was constantly secreted from glioma cells (U251) and radiation had a little influence on the secretion of VEGF by residual glioma cells even after 1-4 Gy irradiation. Glioma cell proliferation was not suppressed by anti-VEGF antibody (bevacizumab) alone. In vivo study: tumor growth delay was induced by carbon ion beam irradiation, but not evident by anti-VEGF antibody (bevacizumab) alone. Residual tumor cells after carbon ion irradiation were relatively larger than no-treated cells and intensely CD133-positive.

Academic Significance and Societal Importance of the Research Achievements

悪性の神経系脳腫瘍の治療抵抗性を再確認した上で、最近注目されている高LETの重粒子線（炭素イオン線）治療、分子標的治療のひとつである抗VEGF抗体（ベバシズマブ）、そしてこれらの併用療法について、その有用性を培養細胞レベルとマウスの組織レベルで検討したが、現状の臨床とほぼ同様の結果で、併用療法の有意な有用性を明確にすることはできなかった。神経系腫瘍幹細胞の関与とそれを標的とした治療の有用性についても検討したが、臨床における有用性を積極的に示唆することまではできず、この難治性腫瘍に対する研究と対策の更なる促進が必要なことが示された。

Research Products

• [Presentation] 悪性神経膠腫を標的とした重粒子線と抗VEGF抗体併用の有効性 (2018)
  • Author(s): 長谷川正俊
  • Organizer: 放射線医学総合研究所 平成29年度HIMAC共同利用研究成果発表会
• [Presentation] Effect of Heavy Ion Beams on Cancer Stem-like Cells in Human Ependymoblastoma (2017)
  • Author(s): Masatoshi Hasegawa, Nobumasa Fujitani, Sachiko Miura, Kaori Yamaki, Emiko Shimoda, Kazuya Inoue, Nobuhide Wakai, Tatsuya Ohno, Masaru Wakatsuki, Takeshi Murakami
  • Organizer: 7th International Society of Radiation Neurobiology Conference (ISRN 2017)
  • Int'l Joint Research
• [Presentation] Growth Arrest and Cancer Stem Cell Marker Expression Following High-Dose X-ray or Carbon Ion Beam Irradiation (2015)
  • Author(s): Hasegawa M, Fujitani N, Wakai N, Inoue K, Shimoda E, Inoue M, Matsui Y, Asakawa I, Takeda M, Wakatsuki M, Murakami T
  • Organizer: ASTRO 57th Annual meeting
  • Place of Presentation: San Antonio, U.S.A.
  • Year and Date: 2015-10-19
  • Int'l Joint Research
• [Presentation] Cancer Stem Cell Markers and Growth Fractions in Human Brain Tumor Following Heavy Ion Irradiation (2015)
  • Author(s): Masatoshi Hasegawa, Nobumasa Fujitani, Emiko Shimoda, Kazuya Inoue, Nobuhide Wakai, Masahiro Morimoto, Isao Asakawa, Tetsuro Tamamoto, Masaru Wakatsuki
  • Organizer: ICRR 2015
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2015-05-28
  • Int'l Joint Research