Overcoming resistance to angiogenic therapy in GBM: development of anti-invasiveness treatment for residual tumor cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03768
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: The University of Tokyo
• Principal Investigator: Soda Yasushi 東京大学, 定量生命科学研究所, 特任准教授 (00361618)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: グリオブラストーマ / 抗血管療法 / 腫瘍浸潤 / 腫瘍特異的代謝 / 解糖系

Outline of Final Research Achievements

Glioblastoma (GBM) is the most malignant and incurable brain tumor. Regardless of its vigorous angiogenesis, GBM was highly resistant to anti-angiogenic therapies which brought enhanced invasiveness. To overcome this resistance, we attempted to develop new therapeutic approaches in this study. Since tumor cells are dependent on glycolysis-predominant cellular metabolism, we targeted glycolysis with its inhibitor. The glycolysis inhibitor efficiently induced toxicity in GBM cells, particularly in GBM stem cells. It inhibited invasiveness as well, suggesting the usefulness in relief of anti-angiogenic therapy resistance. In addition, we identified a pro-invasive factor (PIF) in GBM. Inhibition of its expression significantly inhibited enhanced invasiveness and extended survival in GBM mouse models, suggesting that this factor is a promising target to conquer the anti-angiogenic therapy resistance. We will develop PIF inhibitors by using screening systems established in this study.

Free Research Field

腫瘍学、腫瘍治療学、遺伝子治療学、ウイルス学、血液学

Academic Significance and Societal Importance of the Research Achievements

GBMは最も悪性度の高い脳腫瘍であり、生存期間中央値は1年半に満たない。治療成績は数十年間ほとんど向上しておらず、新規治療法開発は喫緊の課題である。本研究成果は、既存治療法とは機序の異なる治療法である、代謝改変療法および浸潤性促進因子抑制法が抗血管療法抵抗性克服に有用であることを示唆するものである。GBM治療開発における新たな可能性を示したものであり、学術的・社会的意義は高いと考えられる。