Investigation of putative roles for GSK3b in glioblastoma stemness phenotype and the underlying biological mechanisms

Studies in vitro and in animal model were carried out complementary to optimize treatment of glioblastoma (GBM) by enhancing anti-tumor effect by combination of GSK3β inhibition and temozolomide (TMZ). For in vitro study, we examined effect of GSK3β inhibition and TMZ on patient derived GBM stem-like cells (SCs). I found that GSK3β inhibition enhances effect of TMZ against GBM-SCs and participate in regulation of GBM stemness phenotype. For animal model study, I have developed software pharmacokinetics model and determined optimal concentration of GSK3β inhibitor for continuous intra-tumor infusion by subcutaneous pumps for treatment of orthotopic GBM models and examined the effects of continuous intra-tumor infusion of GSK3β inhibitor, against GBM in mice bearing human GBM-SCs. Our experiments showed that GSK3β inhibition is effective for treatment of experimental GBM generated by inoculation of most malignant GBM-SCs characterized by shortest survival in control animals. We investigated biological mechanisms by which GSK3β regulate GBM stemness phenotype and revealed changes in stem cell markers’ expression in GBM-SCs under GSK3β inhibition, which can be associated with regulation of GBM stemness phenotype by GSK3β via multiple signaling pathways.研究課題/領域番号:18K16553, 研究期間(年度):2018-04-01 - 2020-03-31出典：「Investigation of putative roles for GSK3b in glioblastoma stemness phenotype and the underlying biological mechanisms」研究成果報告書 課題番号18K16553（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-18K16553/）を加工して作