Development of therapeutic methods targeting the GTP metabolic pathway activated in malignant glioma

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08939
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Sumita Kazutaka 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (70752830)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 悪性神経膠腫 / GTP

Outline of Final Research Achievements

In this study, we investigated treatments targeting Guanosine triphosphate (GTP) metabolism in malignant gliomas. Mycophenolic acid (MPA) is a drug that has been shown to reduce GTP relative to cell lines. This MPA significantly reduces the intracellular GTP level by suppressing the production of Inosine-5'-monophosphate dehydrogenase (IMPDH). The effect of MPA was examined on tumor stem cells prepared from brain tumor cell lines and surgically removed samples, and the tumor cell proliferation inhibitory effect of MPA was obtained. The tumor was divided and collected by surgery with reference to imaging findings such as MRI and PET. Tumors in this methionine accumulated area were shown to have increased IMPDH2 in the mRNA microarray. In malignant glioma, high expression of IMPDH2 increased the ability to synthesize rRNA and tRNA. It was found that suppression of IMPDH2 has an effect of suppressing cell proliferation.

Free Research Field

脳神経外科

Academic Significance and Societal Importance of the Research Achievements

原発性脳腫瘍のうちもっとも悪性度の高い神経膠芽腫は近年化学療法の発展に伴ってその予後は改善しつつあるものの、生存期間中央値は約15ヶ月であり治療困難な疾患である。この悪性神経膠腫の治療が困難な原因は、脳には機能の局在があり全摘出することが困難であること、分子生物学的多様性による治療抵抗性、さらには脳血流関門などによる薬剤の腫瘍への到達性が低いことが挙げられている。現時点で生命予後を著明に改善させる分子標的薬はなく、治療成績の向上には新規の治療が必要である。本研究において増殖する細胞の多くで活性化しているIMPDH2の治療標的としての可能性が示された。