TY - THES

T1 - CIZ1 as a therapeutic target for glioblastoma

AU - Paxton, Matheson

PY - 2025

Y1 - 2025

N2 - Glioblastoma is a devastating disease with a median survival of 12 – 15 months. It is the most common brain tumour in adults and current standard treatments remain poor. Surgery and radiotherapy only improve patient prognosis short term (12.1 months median survival) and the only available chemotherapy (TMZ) extends median survival to just 14.6 months. Resistance mechanisms may explain the poor response of grade IV, IDH wildtype glioblastomas to TMZ. CIZ1 is a nuclear protein with DNA replication, epigenetic maintenance, and genome stability functions. CIZ1 is overexpressed in many cancers, including glioblastoma, and is evidenced to drive tumourigenesis. CDK inhibition therapyhas showed recent promise in the treatment of cancer and some FDA approved CDK4/6 inhibitors are now used in routine breast cancer treatment. CDK inhibitors have been trialled in glioblastoma patients, showing some efficacy, however it is hypothesised that CDK inhibition may reduce CIZ1 levels to reduce glioblastoma growth. Our aim was to demonstrate the efficacy of CDK inhibitors on reducing proliferation and their toxicity in glioblastoma cultures, as well as showing reduced CIZ1 protein expression and comparing data to that of normal glia. Here, we assess the effect of a panel of six CDK inhibitors on glioblastoma (U-87 MG and BTNW914) and normal glia (SVG p12) cell lines. CDK inhibitioncauses significantly reduced glioblastoma cell proliferation compared with vehicle controls and normal glia. Cell cycle arrest and cell death is also observed in both in 2D and 3D glioblastoma cell culture. The effect on CIZ1 levels has proved inconclusive and requires further investigation. Overall, these data identify that CDK inhibitors have promising efficacy in reducing proliferation and increasing cell death in glioblastoma models in vitro and should be further investigated in pre-clinical models.

AB - Glioblastoma is a devastating disease with a median survival of 12 – 15 months. It is the most common brain tumour in adults and current standard treatments remain poor. Surgery and radiotherapy only improve patient prognosis short term (12.1 months median survival) and the only available chemotherapy (TMZ) extends median survival to just 14.6 months. Resistance mechanisms may explain the poor response of grade IV, IDH wildtype glioblastomas to TMZ. CIZ1 is a nuclear protein with DNA replication, epigenetic maintenance, and genome stability functions. CIZ1 is overexpressed in many cancers, including glioblastoma, and is evidenced to drive tumourigenesis. CDK inhibition therapyhas showed recent promise in the treatment of cancer and some FDA approved CDK4/6 inhibitors are now used in routine breast cancer treatment. CDK inhibitors have been trialled in glioblastoma patients, showing some efficacy, however it is hypothesised that CDK inhibition may reduce CIZ1 levels to reduce glioblastoma growth. Our aim was to demonstrate the efficacy of CDK inhibitors on reducing proliferation and their toxicity in glioblastoma cultures, as well as showing reduced CIZ1 protein expression and comparing data to that of normal glia. Here, we assess the effect of a panel of six CDK inhibitors on glioblastoma (U-87 MG and BTNW914) and normal glia (SVG p12) cell lines. CDK inhibitioncauses significantly reduced glioblastoma cell proliferation compared with vehicle controls and normal glia. Cell cycle arrest and cell death is also observed in both in 2D and 3D glioblastoma cell culture. The effect on CIZ1 levels has proved inconclusive and requires further investigation. Overall, these data identify that CDK inhibitors have promising efficacy in reducing proliferation and increasing cell death in glioblastoma models in vitro and should be further investigated in pre-clinical models.

U2 - 10.17635/lancaster/thesis/2637

DO - 10.17635/lancaster/thesis/2637

M3 - Master's Thesis

PB - Lancaster University

ER -