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ニューロサイエンスの旅 Vol. 59

当科の共同研究者、杉森道也先生の研究成果がOncotarget誌に掲載されました。ここ数年、われわれが研究を進めているTOPK inhibitor, OTS964が悪性グリオーマの腫瘍幹細胞(glioma stem cell)の生物学的活性を抑制することは既に報告していますが、現在、臨床でも使用されている化学療法剤テモゾロミドを併用することで、腫瘍幹細胞に効果がさらに増強されることが判明しました。

The combined efficacy of OTS964 and temozolomide for reducing the size of power-law coded heterogeneous glioma stem cell populations.
Michiya Sugimorii
, Yumiko Hayakawa, Ryoi Tamura and Satoshi Kuroda
*These authors contributed equally to this work

ABSTRACT
Glioblastoma resists chemotherapy then recurs as a fatal space-occupying lesion. To improve the prognosis, the issues of chemoresistance and tumor size should be addressed. Glioma stem cell (GSC) populations, a heterogeneous power-law coded population in glioblastoma, are believed to be responsible for the recurrence and progressive expansion of tumors. Thus, we propose a therapeutic strategy of reducing the initial size and controlling the regrowth of GSC populations which directly facilitates initial and long-term control of glioblastoma recurrence. In this study, we administered an anti-glioma/GSC drug temozolomide (TMZ) and OTS964, an inhibitor for T-Lak cell originated protein kinase, in combination (T&O), investigating whether together they efficiently and substantially shrink the initial size of power-law coded GSC populations and slow the long-term re-growth of drug-resistant GSC populations. We employed a detailed quantitative approach using clonal glioma sphere (GS) cultures, measuring sphere survivability and changes to growth during the self-renewal. T&O eliminated self-renewing GS clones and suppressed their growth. We also addressed whether T&O reduced the size of self-renewed GS populations. T&O quickly reduced the size of GS populations via efficient elimination of GS clones. The growth of the surviving T&O-resistant GS populations was continuously disturbed, leading to substantial long-term shrinkage of the self-renewed GS populations. Thus, T&O reduced the initial size of GS populations and suppressed their later regrowth. A combination therapy of TMZ and OTS964 would represent a novel therapeutic paradigm with the potential for long-term control of glioblastoma recurrence via immediate and sustained shrinkage of power-law coded heterogeneous GSC populations.

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