Intraoperative treatment targeting tumor-specific podoplanin for malignant gliomas

• Project/Area Number: 19K09476
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Niigata University
• Principal Investigator: Natsumeda Manabu 新潟大学, 脳研究所, 助教 (00515728)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: NIR-PIT / Podoplanin / Glioma / Glioblastoma / Photoimmunotherapy / Laser / 近赤外線光線免疫療法 / 脳腫瘍 / 抗体 / 表面抗原 / 術中療法 / ポドプラニン / 悪性神経膠腫 / 神経膠腫 / 膠芽腫 / 術注療法 / 近赤外光線免疫療法 / グリオーマ

Outline of Research at the Start

悪性神経膠腫は極めて予後不良で、新規治療の開発が待たれる。その主因は、正常脳に浸潤する腫瘍細胞が手術で残存するからとされる。近年、近赤外光線免疫療法（NIR－PIT）という腫瘍細胞の表面抗原を標的し腫瘍細胞のみを破壊する抗原特異的免疫療法が注目されている。腫瘍特異抗体を蛍光標識することで術中の残存腫瘍の評価にも利用でき、NIR－PITの実現は神経膠腫に革命的な治療の進歩をもたらす可能性がある。一方でポドプラニンは悪性神経膠腫に高頻度に発現する膜貫通型蛋白である。本研究は、悪性神経膠腫に対して腫瘍特異的ポドプラニン抗体を用いたNIR-PITの実現化を目的とし、ヒト化抗体を用いた臨床応用を目指す。

Outline of Final Research Achievements

We established an intraoperative antibody treatment (near-infrared photoimmunotherapy) for glioblastomas, a very malignant brain tumor, by targeting the surface antigen podoplanin. First, we assessed podoplanin expression in glioblastomas and found that podoplanin is expressed in over 90% of all glioblastomas. Next, we used 3 podoplanin-positive and 3 podoplanin-negative glioblastoma cell lines and found that the podoplanin antigen was expressed at the surface of podoplanin-positive cells. Lastly, we successfully performed in vitro and in vivo experiments by administering podoplanin-IR700 complex to podoplanin positive cells and xenograft mice and treating with infrared laser. Next, we seek clinical application of this method.

Academic Significance and Societal Importance of the Research Achievements

近赤外線光線免疫療法はEGFR増幅頭頸部癌やHER2陽性乳癌で臨床応用されつつあるが、膠芽腫への臨床応用は未だされていない。今回、我々の研究により膠芽腫に特異的な表面マーカーで正常脳には殆ど発現していないポドプラニンを同定し、それを標的とした近赤外線光線免疫療法に成功した。膠芽腫は極めて予後不良な脳腫瘍であり、その新規治療法の確立は急務である。臨床応用まで実現すれば、膠芽腫の予後が飛躍的に向上する可能性が有り、社会的意義は高い。

Research Products

• [Journal Article] HSP90 inhibition overcomes resistance to molecular targeted therapy in BRAFV600E mutant high-grade glioma (2022)
  • Author(s): Sasame J, Ikegaya N, Kawazu M, Natsumeda M, Hayashi T, Isoda M, Satomi K, Tomiyama A, Oshima A, Honma H, Miyake Y, Takabayashi K, Nakamura T, Ueno T, Matsushita Y, Iwashita H, Kanemaru Y, Murata H, Ryo A, Terashima K, Yamanaka S, Fujii Y, Mano H, Komori T, Ichimura K, Cahill DP, Wakimoto H, Yamamoto T, Tateishi K.
  • Journal Title: Clin Cancer Res Volume: 印刷中 Issue: 11 Pages: 2425-2439
  • DOI: 10.1158/1078-0432.ccr-21-3622
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel Repositioning Therapy for Drug-Resistant Glioblastoma: In Vivo Validation Study of Clindamycin Treatment Targeting the mTOR Pathway and Combination Therapy with Temozolomide (2022)
  • Author(s): Eda T, Okada M, Ogura R, Tsukamoto Y, Kanemaru Y, Watanabe J, On J, Aoki H, Oishi M, Takei N, Fujii Y, Natsumeda M.
  • Journal Title: Cancers (Basel) Volume: 14 Issue: 3 Pages: 770-770
  • DOI: 10.3390/cancers14030770
  • Peer Reviewed / Open Access
• [Journal Article] Predicting BRAF V600E mutation in glioblastoma: utility of radiographic features (2021)
  • Author(s): Natsumeda M, Chang M, Gabdulkhaev R, Takahashi H, Tsukamoto Y, Kanemaru Y, Okada M, Oishi M, Okamoto K, Rodriguez FJ, Kakita A, Fujii Y, Schreck KC.
  • Journal Title: Brain Tumor Pathol Volume: 38 Issue: 3 Pages: 228-233
  • DOI: 10.1007/s10014-021-00407-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GLI3?Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma (2021)
  • Author(s): Natsumeda Manabu、Miyahara Hiroaki、Yoshimura Junichi、Nakata Satoshi、Tsukamoto Yoshihiro、Okada Masayasu、Oishi Makoto、Hirato Junko、Wataya Takafumi、Tateishi Kensuk、Rodriguez Fausto J、Hovestadt Volker、Suva Mario L、Taylor Michael D、Eberhart Charles G、Fujii Yukihiko、et al.
  • Journal Title: Journal of Neuropathology & Experimental Neurology Volume: 80 Issue: 2 Pages: 129-136
  • DOI: 10.1093/jnen/nlaa141
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Low Detection Rate of H3K27M Mutations in Cerebrospinal Fluid Obtained from Lumbar Puncture in Newly Diagnosed Diffuse Midline Gliomas (2021)
  • Author(s): On Jotaro、Natsumeda Manabu、Watanabe Jun、Saito Shoji、Kanemaru Yu、Abe Hideaki、Tsukamoto Yoshihiro、Okada Masayasu、Oishi Makoto、Yoshimura Junichi、Kakita Akiyoshi、Fujii Yukihiko
  • Journal Title: Diagnostics Volume: 11 Issue: 4 Pages: 681-681
  • DOI: 10.3390/diagnostics11040681
  • Peer Reviewed / Open Access
• [Journal Article] A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma (2020)
  • Author(s): Tateishi Kensuke、Miyake Yohei、Kawazu Masahito、Sasaki Nobuyoshi、Nakamura Taishi、Sasame Jo、Yoshii Yukie、Ueno Toshihide、Miyake Akio、Matsushita Yuko、Shiba Norio、Udaka Naoko、Ohki Kentaro、Fink Alexandria L.、Tummala Shilpa S.、Natsumeda Manabu、Miller Julie J.、Fujii Yukihiko、et al
  • Journal Title: Cancer Research Volume: 80 Issue: 23 Pages: 5330-5343
  • DOI: 10.1158/0008-5472.can-20-2425
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas (2019)
  • Author(s): Hideaki Abe, Manabu Natsumeda1, Masayasu Okada, Jun Watanabe, Yoshihiro Tsukamoto, Yu Kanemaru, Junichi Yoshimura, Makoto Oishi, Rintaro Hashizume, Akiyoshi Kakita and Yukihiko Fujii
  • Journal Title: Frontiers in Oncology Volume: 9 Pages: 1-10
  • DOI: 10.3389/fonc.2019.01568
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Podoplanin expression and IDH-wildtype status predicts venous thromboembolism in patients with high-grade gliomas in the early postoperative period. (2019)
  • Author(s): Watanabe J, Natsumeda M, Okada M, Kanemaru Y, Tsukamoto Y, Oishi M, Kakita A, Fujii Y.
  • Journal Title: World Neurosurg. Volume: 印刷中 Pages: 2275-2281
  • DOI: 10.1016/j.wneu.2019.05.049
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of circulating tumor DNA between body fluids in patients with primary central nervous system lymphoma (2019)
  • Author(s): Watanabe Jun、Natsumeda Manabu、Kanemaru Yu、Okada Masayasu、Oishi Makoto、Kakita Akiyoshi、Fujii Yukihiko
  • Journal Title: Leukemia & Lymphoma Volume: 60 Issue: 14 Pages: 3587-3589
  • DOI: 10.1080/10428194.2019.1639169
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy (2019)
  • Author(s): Kanemaru Yu、Natsumeda Manabu、Okada Masayasu、Saito Rie、Kobayashi Daiki、Eda Takeyoshi、Watanabe Jun、Saito Shoji、Tsukamoto Yoshihiro、Oishi Makoto、Saito Hirotake、Nagahashi Masayuki、Sasaki Takahiro、Hashizume Rintaro、Aoyama Hidefumi、Wakai Toshifumi、Kakita Akiyoshi、Fujii Yukihiko
  • Journal Title: Acta Neuropathologica Communications Volume: 7 Issue: 1 Pages: 119-119
  • DOI: 10.1186/s40478-019-0774-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EGFRvIII Is Expressed in Cellular Areas of Tumor in a Subset of Glioblastoma (2019)
  • Author(s): Nozawa T , Okada M, Natsumeda M, Eda T, Abe H, Tsukamoto Y, Okamoto K, Oishi M, Takahashi H, Fujii Y, Kakita A
  • Journal Title: Neurologia medico-chirurgica Volume: 59 Issue: 3 Pages: 89-97
  • DOI: 10.2176/nmc.oa.2018-0078
  • NAID: 130007612662
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High detection rate of MYD88 mutations in cerebrospinal fluid from patients with central nervous system lymphomas (2019)
  • Author(s): Jun Watanabe, Manabu Natsumeda, Masayasu Okada, Daiki Kobayashi, Yu Kanemaru, Yoshihiro Tsukamoto, Makoto Oishi, Akiyoshi Kakita, Yukihiko Fujii
  • Journal Title: JCO Precision Oncology Volume: 3 Issue: 3 Pages: 1-13
  • DOI: 10.1200/po.18.00308
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 当科における光線力学療法の経験および次世代への挑戦 (2021)
  • Author(s): 棗田 学
  • Organizer: Laser Week in Tokyo II
• [Presentation] プレシジョン・メディシンを念頭に入れた脳腫瘍モデル確立の試み (2021)
  • Author(s): 棗田 学
  • Organizer: 第35回Japan Neurosurgery English Forum
• [Presentation] Less invasive diagnosis and precision medicine in malignant brain tumors (2021)
  • Author(s): 棗田 学
  • Organizer: 第41回日本脳神経外科コングレス学術総会
• [Presentation] Establishment of cell lines and xenografts for the realization of precision medicine in brain tumor patients (2021)
  • Author(s): 棗田 学
  • Organizer: 第10回生理研-霊長研-脳研国際シンポジウム
• [Presentation] 悪性神経膠腫における術後静脈血栓塞栓症危険因子の検討 -ポドプラニンとIDH変異の関係- (2019)
  • Author(s): 棗田 学
  • Organizer: 第37回日本脳腫瘍病理学会学術集会