Development of a novel targeted internal radiotherapy strategy by co-targeting of cancer cell integrin, angiogenesis, and hypoxic environment

• Project/Area Number: 18K07776
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52040:Radiological sciences-related
• Research Institution: National Institutes for Quantum Science and Technology
• Principal Investigator: Jin Zhao-Hui 国立研究開発法人量子科学技術研究開発機構, 量子医科学研究所 分子イメージング診断治療研究部, 主任研究員 (70324150)
• Project Period (FY): 2018-04-01 – 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 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: がん不均一性 / 標的アイソトープ治療 / インテグリン / 血管新生 / 低酸素環境 / 低pH / 放射性医薬品 / 同時標的 / 標的放射線内照射療法 / RI内用療法 / 腫瘍内不均一性 / 併用治療戦略 / 腫瘍内放射能分布 / αVβ3インテグリン / 腫瘍内低酸素環境 / 放射線内照射療法 / 放射線内用療法 / 腫瘍内低酸素領域

Outline of Final Research Achievements

In this research, a series of studies were conducted on the development of a novel targeted radionuclide therapy (TRT) strategy that simultaneously targets cancer cell integrins, angiogenesis, and the hypoxic environment. Using human tumor xenograft models, we confirmed that the intratumoral distributions (ITDs) of 64Cu-RaftRGD, a β-particle emitting therapeutic agent targeting αVβ3 integrins overexpressed on both cancer cells and angiogenic endothelial cells, and 64Cu-ATSM, a β-particle emitting therapeutic agent targeting hypoxia, were discordant but spatially complementary, and that the combination of the two drugs improved the therapeutic efficacy even though the total radioactivity uptake was lower. The complementary ITDs of fluorescent dye Cy5.5 or 64Cu-labeled RaftRGD and the representative hypoxia probe pimonidazole were demonstrated in various tumor models, providing the basic rationale for the combination TRT concept that simultaneously targets integrins and hypoxia.

Academic Significance and Societal Importance of the Research Achievements

腫瘍組織内の不均一性は、がんの治療抵抗性の根本的な原因であると認識されつつある。標的放射線内照射療法の治療効果を高めるために、投与線量の増加や化学療法などの他の治療法との併用が一般的に行われている。本研究課題は、腫瘍内分布が異なるが相補的な2つの放射性治療薬剤を用いた併用治療戦略において、腫瘍組織における細胞致死的な放射能の分布を改善することで治療効果が向上することを明確に示した世界初の研究である。本研究の成果は、難治性がんに対する腫瘍内不均一性を克服する新たな治療戦略の開発に役立つものであり、副作用の少ないより有効ながん治療法の開発に大きな社会的意義があると考えられる。

Research Products

• [Int'l Joint Research] University Grenoble Alpes/CNRS/University of Montpellier(フランス)
• [Int'l Joint Research] University Grenoble Alpes/University of Montpellier(フランス)
• [Int'l Joint Research] University Grenoble Alpes(フランス)
• [Journal Article] Multiplexed Imaging Reveals the Spatial Relationship of the Extracellular Acidity-Targeting pHLIP with Necrosis, Hypoxia, and the Integrin-Targeting cRGD Peptide (2022)
  • Author(s): Zhao-Hui Jin, Atsushi B Tsuji, Melissa Degardin, Pascal Dumy, Didier Boturyn, and Tatsuya Higashi
  • Journal Title: Cells Volume: 11 Issue: 21 Pages: 3499-3499
  • DOI: 10.3390/cells11213499
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Radiotheranostic Agent 64Cu-cyclam-RAFT-c(-RGDfK-)4 for Management of Peritoneal Metastasis in Ovarian Cancer (2020)
  • Author(s): Jin Zhao-Hui、Tsuji Atsushi B.、Degardin Melissa、Sugyo Aya、Obara Satoshi、Wakizaka Hidekatsu、Nagatsu Kotaro、Hu Kuan、Zhang Ming-Rong、Dumy Pascal、Boturyn Didier、Higashi Tatsuya
  • Journal Title: Clinical Cancer Research Volume: 26 Issue: 23 Pages: 6230-6241
  • DOI: 10.1158/1078-0432.ccr-20-1205
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Uniform intratumoral distribution of radioactivity produced using two different radioagents, 64Cu-cyclam-RAFT-c(-RGDfK-)4 and 64Cu-ATSM, improves therapeutic efficacy in a small animal tumor model (2018)
  • Author(s): Jin ZH, Tsuji AB, Degardin M, Sugyo A, Yoshii Y, Nagatsu K, Zhang MR, Fujibayashi Y, Dumy P, Boturyn D, Higashi T
  • Journal Title: EJNMMI Research Volume: 8 (1) Issue: 1 Pages: 54-54
  • DOI: 10.1186/s13550-018-0407-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A radiotheranostic study for strategic treatment of ovarian cancer peritoneal metastases using the all-in-one multimeric radiopeptide 64Cu-cyclam-RAFT-c(-RGDfK-)4 (2021)
  • Author(s): Zhao-Hui Jin, Atsushi B. Tsuji, Melissa Degardin, Aya Sugyo, Satoshi Obara, Hidekatsu Wakizaka, Kotaro Nagatsu, Kuan Hu, Ming-Rong Zhang, Pascal Dumy, Didier Boturyn, and Tatsuya Higashi
  • Organizer: 第68回米国核医学・分子イメージング学会（SNMMI2021)
  • Int'l Joint Research
• [Presentation] Uniformed intratumoral distribution of radioactivity produced by using two different radioagents 64Cu-cyclam-RAFT-c(-RGDfK-)4 and 64Cu-ATSM improves therapeutic efficacy in a small animal tumor model (2018)
  • Author(s): Zhao-Hui Jin, Atsushi Tsuji, Melissa Degardin, Aya Sugyo, Yukie Yoshii, Kotaro Nagatsu, Ming-Rong Zhang, Yasuhisa Fujibayashi, Pascal Dumy, Didier Boturyn, and Tatsuya Higashi
  • Organizer: SNMMI 2018 Annual Meeting
  • Int'l Joint Research
• [Funded Workshop] 第68回米国核医学・分子イメージング学会（SNMMI2021） (2021)