Dynamic Imaging of LDH Inhibition in Tumors by 13C-MRI to Treat Colon Cancer

• Project/Area Number: 20K09054
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyoto University
• Principal Investigator: OSHIMA NOBU 京都大学, 医学研究科, 客員研究員 (70571454)
• Co-Investigator(Kenkyū-buntansha): 兵藤 文紀 岐阜大学, 大学院医学系研究科, 特任准教授 (10380693) ; 久森 重夫 京都大学, 医学研究科, 助教 (50534351) ; 板谷 喜朗 京都大学, 医学研究科, 助教 (80814029)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 大腸癌 / 癌代謝 / LDH / LDH阻害薬 / 超偏極13C-MRI / ピルビン酸代謝 / LDH阻害 / 解糖系 / OxPhos / 膵癌 / 代謝 / 超偏極13CMRI / 代謝阻害療法 / がん代謝 / 乳酸脱水素酵素 / ワールバーグ効果 / 胃癌 / LDH阻害剤 / セラノスティクス

Outline of Research at the Start

超偏極13C-MRIを用いて、1:腫瘍内LDH活性可視化による“解糖系依存型”癌の抽出、2:LDH阻害剤の癌組織内でのLDH阻害効果の評価、3:LDH阻害による抗腫瘍効果の有無、を明らかにし、画像診断によるLDH阻害治療の選択が可能か検証する。本研究は、13C-MRIと新規開発したLDH阻害剤を用いた癌代謝標的治療への応用研究であり、画像診断と有効治療法選択を同時に行う手法で新規代謝標的治療モデルの確立をめざすものである。

Outline of Final Research Achievements

Pyruvate metabolism involves two major pathways, the "glycolytic" and the "OxPhos" pathways. Colon cancer cells also showed enhanced pyruvate metabolism in response to high energy demand, but the balance between the "glycolytic" and "OxPhos" pathways in the cells was different in each cell line. And, it was also revealed that there was metabolic plasticity between the two pathways. The response to each metabolic pathway inhibitor was also different in each cell line, and the anti-tumor effect obtained was also different.
In this study, we used a novel medical imaging technique: hyperpolarized 13C-MRI and newly developed metabolic inhibitors to evaluate metabolic characteristics ("glycolytic" and "OxPhos" status) in colorectal cancer tissues in vivo and to select treatment according to these characteristics. The method also enables the determination of drug efficacy and treatment prediction at a time.

Academic Significance and Societal Importance of the Research Achievements

解糖系の亢進はがん代謝の特徴とされているが、大腸癌細胞内でピルビン酸代謝には解糖系とOxPhos系の相互の可塑性が存在し、この可塑性を標的とすることが重要であることを明らかにした。
新規開発された代謝阻害剤と超偏極13C-MRI用いて、治療効果予測を行う手法を確立した。この手法は大腸がん診断初期に治療効果判定（予測）を行える利点があること、及び、他の抗がん剤でも応用可能と考えられる。進行大腸がんや非切除因子をもつ大腸がん患者に対する治療戦略を診断早期に決定でき、適切な外科的手術介入の範囲・タイミングをより詳細に決定できるなどの効果をもたらし、大腸がん治療の成績向上への貢献が期待される。

Research Products

• [Journal Article] Timing of real‐time indocyanine green fluorescence visualization for lymph node dissection during laparoscopic colon cancer surgery (2023)
  • Author(s): Hiromitsu Kinoshita, Kenji Kawada, Yoshiro Itatani, Ryosuke Okamura, Nobu Oshima, Tomoaki Okada, Koya Hida, Kazutaka Obama
  • Journal Title: Langenbeck's Archives of Surgery Volume: 408 Issue: 1
  • DOI: 10.1007/s00423-023-02808-5
  • Peer Reviewed
• [Journal Article] Structure-guided design enables development of a hyperpolarized molecular probe for the detection of aminopeptidase N activity in vivo (2022)
  • Author(s): Yutaro Saito, Hiroyuki Yatabe, Iori Tamura, Yohei Kondo, Ryo Ishida, Tomohiro Seki, Keita Hiraga, Akihiro Eguchi, Yoichi Takakusagi, Keisuke Saito, Nobu Oshima, Hiroshi Ishikita, Kazutoshi Yamamoto, Murali C. Krishna, Shinsuke Sando
  • Journal Title: Science advances Volume: 8 Issue: 13
  • DOI: 10.1126/sciadv.abj2667
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Application of Hyperpolarized 13C-MRI to Cancer Treatment: Real-Time Monitoring of Pyruvate Metabolic Fluxes in Vivo and Targeting Intra-Tumor Metabolic Plasticity with Small Molecules (2022)
  • Author(s): Nobu OSHIMA, et al.
  • Journal Title: Journal of the American College of Surgeons Volume: 235 Issue: 5 Pages: S5-S16
  • DOI: 10.1097/01.xcs.0000893008.02117.d2
  • Peer Reviewed / Open Access
• [Journal Article] Real-Time insight into in vivo redox status utilizing hyperpolarized [1- 13 C] N-acetyl cysteine (2021)
  • Author(s): Yamamoto K, Opina A, Sail D, Blackman B, Saito K, Brender JR, Malinowski RM, Seki T, Oshima N, Crooks DR, Kishimoto S, Saida Y, Otowa Y, Choyke PL, Jan H. Ardenkjr-Larsen, Mitchell JB, Linehan WM, Swenson RE & Krishna MC
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 12155-12155
  • DOI: 10.1038/s41598-021-90921-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 超偏極13CMRIを用いた膵癌に対するLDH阻害治療効果の動的な可視化 (2020)
  • Author(s): 大嶋野歩, 岸本俊, 石田諒, 愛須佑樹, 岡田倫明, 錦織達人, 板谷喜朗, 久森重夫, 角田茂, 肥田侯矢, 河田健二, 兵藤文紀, 松尾政之, 中本裕士, 小濱和貴, Neckers LM, Krishna MC, 坂井義治
  • Journal Title: 胆と膵 Volume: 41 Pages: 751-6
• [Journal Article] Molecular Imaging of the Tumor Microenvironment Reveals the Relationship between Tumor Oxygenation, Glucose Uptake, and Glycolysis in Pancreatic Ductal Adenocarcinoma (2020)
  • Author(s): Yamamoto Kazutoshi、Brender Jeffrey R.、Seki Tomohiro、Kishimoto Shun、Oshima Nobu、Choudhuri Rajani、Adler Stephen S.、Jagoda Elaine M.、Saito Keita、Devasahayam Nallathamby、Choyke Peter L.、Mitchell James B.、Krishna Murali C.
  • Journal Title: Cancer Research Volume: 80 Issue: 11 Pages: 2087-2093
  • DOI: 10.1158/0008-5472.can-19-0928
  • Peer Reviewed
• [Journal Article] Pyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties (2020)
  • Author(s): Rai Ganesha、Urban Daniel J.、Jana Somnath、Muttil Pavan、Anderson Tamara、Kunda Nitesh K.、Oshima Nobu、Cherukuri Murali、、Dang Chi V.、Stott Gordon M.、Neckers Leonard
  • Journal Title: Journal of Medicinal Chemistry Volume: 63 Issue: 19 Pages: 10984-11011
  • DOI: 10.1021/acs.jmedchem.0c00916
  • Peer Reviewed
• [Journal Article] Laparoscopic left hemicolectomy with regional lymph node navigation and intracorporeal anastomosis for splenic flexure colon cancer (2020)
  • Author(s): Itatani Yoshiro、Kawada Kenji、Hida Koya、Deguchi Yasunori、Oshima Nobu、Mizuno Rei、Wada Toshiaki、Okada Tomoaki、Sakai Yoshiharu
  • Journal Title: International Cancer Conference Journal Volume: 9 Issue: 4 Pages: 170-174
  • DOI: 10.1007/s13691-020-00424-4
  • Peer Reviewed
• [Journal Article] Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy (2020)
  • Author(s): Oshima N, Ishida R, Kishimoto S, Beebe K, Brender J, Yamamoto K, Urban D, Squadrito GL, Crooks D, Jackson J, Joshi A,
  • Journal Title: Cell Reports Volume: 30 Issue: 6 Pages: 1798-1810.e4
  • DOI: 10.1016/j.celrep.2020.01.039
  • Peer Reviewed / Open Access
• [Presentation] Application of Hyperpolarized 13C-MRI to Cancer Treatment: Real-time monitoring of pyruvate metabolic fluxes in vivo and targeting intra-tumor metabolic plasticity with small molecules (2022)
  • Author(s): Nobu Oshima, Yuki Aisu, Ryo Ishida, Shun kishimoto, Shigeo Hisamori, Shigeru Tsunoda, Satoshi Kaihara, Kazutaka Obama, Murali C. Krishna, Len Neckers
  • Organizer: American College of Surgeons, Clinical Congress 2022
  • Int'l Joint Research
• [Presentation] Application of Hyperpolarized 13C-MRI to Cancer Treatment: Real-time monitoring of pyruvate metabolic fluxes in vivo and targeting intra-tumor metabolic plasticity with small molecules (2022)
  • Author(s): Nobu Oshima, Yuki Aisu, Ryo Ishida, Shun kishimoto, Shigeo Hisamori, Shigeru Tsunoda, Satoshi Kaihara, Kazutaka Obama, Murali C. Krishna, Len Neckers
  • Organizer: American College of Surgeons: Owen H Wangensteen Scientific Forum 2022, Excellence in reserach
  • Int'l Joint Research / Invited
• [Presentation] 超偏極13C-MRIによる腫瘍組織内でのピルビン酸代謝の動的観察とセラノスティクスへの展開 (2022)
  • Author(s): 大嶋 野歩, 愛須 佑樹, 久森 重夫, 角田 茂, 兵藤 文紀, 松尾 政之, 板谷 喜朗, 橋田 裕毅, 貝原 聡, 小濱 和貴
  • Organizer: 第77回日本消化器外科学会総会
• [Presentation] 外科医からみた超偏極・代謝 MRI イメージング:ユーザーの視点から (2022)
  • Author(s): 大嶋野歩
  • Organizer: 日本磁気共鳴医学会:スタディグループミーティング「臨床応用を指向する超偏極・代謝 MRIイメージング」
  • Invited
• [Presentation] 消化器癌でのピルビン酸代謝モニタリングと治療応用 (2022)
  • Author(s): 愛須佑樹, 大嶋野歩, 花田圭太, 岡田倫明, 板谷喜朗, 久森重夫, 角田茂, 河田健二, 兵藤文紀, 松尾政之, 小濱和貴
  • Organizer: 第77回日本消化器外科学会総会
• [Presentation] Comprehensive monitoring of pyruvate metabolism in cancer cells and tumors reveals vulnerability to metabolic inhibition therapy with small molecules (2022)
  • Author(s): Nobu Oshima, Yuki Aisu, Shigeo Hisamori, Shigeru Tsunoda, Hiroki Hashida, Kenji Uryuhara, Hiroyuki Kobayashi, Masato Kondo, Koji Kitamura, Satoshi Kaihara, Kazutaka Obama, Krishna C. Murali, Len M. Neckers.
  • Organizer: The AACR Annual Meeting 2022
  • Int'l Joint Research
• [Presentation] A newly designed hyperpolarized molecular probe enables the in vivo detection of aminopeptidase N activity from the tumor regions in animals (2022)
  • Author(s): Hiroyuki Yatabe, Yutaro Saito, Iori Tamura, Yohei Kondo, Ryo Ishida, Tomohiro Seki, Keita Hiraga, Akihiro Eguchi, Yoichi Takakusagi, Keisuke Saito, Nobu Oshima, Hiroshi Ishikita, Kazutoshi Yamamoto, Murali C. Krishna, Shinsuke Sando
  • Organizer: World Molecular Imaging Congress (WMIC) 2022
  • Int'l Joint Research
• [Presentation] 超偏極13C-MRI用いた，薬剤による腫瘍組織内におけるピルビン酸代謝 変容のモニタリング (2021)
  • Author(s): 大嶋野歩, 石田諒, 愛須佑樹, 久森重夫, 板谷喜郎, 兵藤文紀, 松尾政之, 角田茂, 貝原聡, 小濱和貴
  • Organizer: 第76回 日本消化器外科学会総会
• [Presentation] 胃癌におけるピルビン酸代謝のモニタリングと代謝阻害療法の開発 (2021)
  • Author(s): 愛須 佑樹, 大嶋 野歩, 花田 圭太, 岡田 倫明, 板谷 喜朗, 久森 重夫, 角田 茂, 兵藤 文紀, 松尾 政之, 小濱 和貴
  • Organizer: 第76回 日本消化器外科学会総会
• [Presentation] 進行再発大腸癌に対する集学的アプローチの最先端 超偏極13C-MRIによる、大腸癌腫瘍内における代謝反応の動的な可視化 (2021)
  • Author(s): 大嶋 野歩, 兵藤 文紀, 松尾 政之, 角田 茂, 久森 重夫, 板谷 喜郎, 岡田 倫明, 小林 裕之, 橋田 裕毅, 瓜生原 健嗣, 近藤 正人, 北村 好史, 喜多 亮介, 貝原 聡, 小濱 和貴
  • Organizer: 第121回 日本外科学会定期学術集会
• [Presentation] Monitoring of pyruvate metabolism in tumors: application of 13C-MRSI to a novel treatment of targeting cancer metabolism (2021)
  • Author(s): Nobu Oshima, Hiroki Hashida, Shigeo Hisamori, Shigeru Tsunoda, Kazutaka Obama2, Krishna MC, Neckers LM
  • Organizer: The 80th Annual Meeting of the Japanese Cancer Association
• [Presentation] 食道癌におけるこだわりの手術手技 臓器鞘コンセプトに基づくロボット支援胸腔鏡下上縦隔リンパ節郭清 (2021)
  • Author(s): 角田 茂, 久森 重夫, 錦織 達人, 岡村 亮輔, 前川 久継, 大森 敦仁, 板谷 喜朗, 岡田 倫明, 大嶋 野歩, 肥田 侯矢, 河田 健二, 喜安 佳之, 山本 高正, 星野 伸明, 村上 克宏, 樽本 浩司, 小濱 和貴
  • Organizer: 第121回 日本外科学会定期学術集会
• [Presentation] MRIを用いた大腸癌におけるセラノスティクスー超偏極13C-MRIを用いた腫瘍内における代謝阻害剤効果のDynamic Monitoring～ (2020)
  • Author(s): 大嶋 野歩, 小濱 和貴, 河田 健二, 肥田 候矢, 久森 重夫, 出口 靖記, 板谷 喜郎, 水野 礼, 和田 聡朗, 錦織 達人, 奥知 慶久, 岡田 倫明, 我如古 理規, Krishna Murali, Neckers Leonard, 坂井 義治
  • Organizer: 第120回日本外科学会
• [Presentation] 大嶋野歩, 愛須佑樹, 岡田倫明, 板谷喜郎, 角田茂, 貝原聡, 小濵和貴 (2020)
  • Author(s): 外科医から見た、超偏極技術を用いた代謝イメージングの臨床応用への期待と展望 ～何を見たくて何がしたいのか～
  • Organizer: 量子生命科学会第２回大会
  • Invited
• [Presentation] 超偏極13C-MRIを用いた，LDH阻害剤およびメトホルミンの大腸癌組織内薬剤効果の可視化と癌治療への応用 (2020)
  • Author(s): 大嶋野歩, 岡田 倫明, 板谷 喜朗, 出口 靖記, 肥田 侯矢, 河田 健二, Murali Krishna, Leonard Neckers, 小濱 和貴, 坂井義治
  • Organizer: 第75回日本消化器外科学会
• [Presentation] Monitoring of a novel LDH inhibitor and mitochondrial inhibitor efficacy in vivo in a glycolytic pancreatic cancer model using hyperpolarized13C MRI (2020)
  • Author(s): Nobu Oshima, Ryo Ishida, Shun Kishimoto, Jeffrey R. Brender, Tomoaki Okada, Kazuataka Obama, Yoshiharu Sakai, Murali C. Krishna and Leonard M. Neckers
  • Organizer: AACR Annual Meeting 2020
  • Int'l Joint Research
• [Presentation] Real-time Monitoring of in vivo free radical scavengers through hyperpolarized [1-13C] N-acetyl cysteine (2020)
  • Author(s): K. Yamamoto, A. Opina, K. Saito, RM Malinowski, T. Seki, N. Oshima, D. Sail, JR Brender, S Kishimoto, N Deva, JH A-Larsen, JB Mitchell, RE Swenson, MC Krishna
  • Organizer: ISMRM & SMRT Virtual Conference 2020
  • Int'l Joint Research
• [Presentation] Novel Real-time Hyperpolarized 13C Metabolic Tracer Probes γ-Glutamyl Transferase Activities in vivo Tumor Xenografts (2020)
  • Author(s): T. Seki, K. Yamamoto, N. Oshima, M. Itoda, Y. Kondo, Y. Saito, Y. Takakusagi, S. Kishimoto, JR Brender, RM Malinowski, JH A-Larsen, H. Nonaka, MC Krishna, S Sando
  • Organizer: ISMRM & SMRT Virtual Conference 2020
  • Int'l Joint Research
• [Remarks] Excellence in Research Awards Recipients 2022
  • URL: https://journals.lww.com/journalacs/Fulltext/2022/11001/American_College_of_Surgeons__Owen_H_Wangensteen.5.aspx
• [Remarks] 京都大学医学部附属病院 消化管外科
  • URL: https://gisurg.kuhp.kyoto-u.ac.jp/info/info-theme/