STAT3 inhibitor, cucurbitacin I, exerts growth-suppressive effects against neuroblastoma cells

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10014
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: The University of Tokyo
• Principal Investigator: Hiwatari Mitsuteru 東京大学, 医学部附属病院, 講師 (40597126)
• Research Collaborator: Takita Junko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 神経芽腫 / STAT3 / cucurbitacin I

Outline of Final Research Achievements

We implemented a high throughput chemical screen in 23 neuroblastoma -derived cell lines, using a curated library of ~450 compounds. We evaluated the therapeutic effects of crizotinib and its combined treatment with JAK-STAT inhibitor (cucurbitacin I) in neuroblastoma cell lines.
In the drug screen, JAK-STAT kinase inhibitor (cucurbitacin I) was the most discriminatory with regard to sensitivity for ALK-mutated cell lines. In neuoblastoma cell lines harboring F1174L or R1275Q-mutated ALK, crizotinib combined with cucurbitacin I enhanced tumor responses and showed synergistic cytotoxicity. Analysis of downstream molecules through MAPK, AKT and STAT3 pathways showed that TGW, a cell line harboring R1275Q-mutated ALK, expressed lower levels of pERK, pAKT and pSTAT3 in combination therapy compared with cells treated with cucurbitacin I or crizotinib alone.

Free Research Field

小児血液・腫瘍学

Academic Significance and Societal Importance of the Research Achievements

従来の化学療法を強化するのみでは難治例白血病や固形腫瘍のような小児がんに対する生存率の改善の期待はできない、更に晩期合併症による生活の質の低下も懸念される。本研究ではSTAT3阻害剤が神経芽腫に対して抗腫瘍効果を認めており、STAT3が神経芽腫のある部分では特異分子として考えられ、直接の標的とする分子標的療法の開発が、それまで難治性であった神経芽腫の生存率を大きく向上させ、また晩期合併症の軽減にも有用であると期待される。本研究の成果が実用化されれば、がん克服者の晩期障害の軽減が達成可能となり、医療費や医療資源の削減が達成され、社会福祉といった観点からも大きな効果がある。