The study for liver cancer specific glycolysis inhibition and efficiency of cancer immunity using novel drug delivery system

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07925
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Sohji Nishina 川崎医科大学, 医学部, 教授 (70550961)
• Co-Investigator(Kenkyū-buntansha): 日野 啓輔 川崎医科大学, 医学部, 特任研究員 (80228741)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: がん / 解糖系 / 2DG / 腫瘍免疫 / PLGA

Outline of Final Research Achievements

1) We established the method for measuring plasma concentration of 2DG in mice using mass spectrometry, and the basis for pharmacokinetic analysis of 2DG-PLGA nanoparticles (2DG-PLGA-NP).
2) Comprehensive evaluation of the mechanism of antitumor immunity by glycolytic inhibition in the tumor microenvironment: 2DG suppressed the proliferation of vascular endothelial cells. In addition, 2DG-PLGA-NP suppressed the invasion of CD11b + Myeloid cells [expressed in T2 tumor-associated macrophages (TAMs)] and suppressed the expression of T2 TAM markers (CD63, Arg1) in hepatocarcinoma (HCC) tissues of immunocompetent mice.
3) HCC cell culture medium in which lactate production was suppressed by 2DG enhanced PD-1 mRNA expression in CD8+ Tcells.

Free Research Field

肝臓学

Academic Significance and Societal Importance of the Research Achievements

2DG-PLGA-NPは、従来の化学療法剤（分子標的薬、免疫チェックポイント阻害剤）と異なる機序での抗腫瘍作用｛殺細胞効果＋腫瘍免疫活性化を有するのみならず、免疫チェックポイント阻害剤（抗PD-1抗体）抵抗性がんモデルに対しても有意な抗腫瘍効果を発揮した。
また、2DG-PLGA-NPは膵癌、大腸癌、悪性黒色腫等のがん細胞移植マウスに対しても抗腫瘍効果を認めており、理論的にも2DGはがん細胞に共通した糖代謝亢進を標的とした抗がん剤であるため、将来的には様々な癌腫に対する適応拡大も可能となる。