TY - THES

T1 - CIZ1 as a therapeutic target for glioblastoma

AU - Paxton, Matheson

PY - 2024

Y1 - 2024

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 and the only available chemotherapy (TMZ) is ineffective in half of the patients that receive it as their tumours develop a resistant phenotype. 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 therapy has 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. 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 inhibition causes reduced glioblastoma cell proliferation, cell cycle arrest and cell death in 2D and 3D culture, as well as a high selectivity over normal glia. 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 reducing 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 and the only available chemotherapy (TMZ) is ineffective in half of the patients that receive it as their tumours develop a resistant phenotype. 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 therapy has 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. 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 inhibition causes reduced glioblastoma cell proliferation, cell cycle arrest and cell death in 2D and 3D culture, as well as a high selectivity over normal glia. 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 reducing cell death in glioblastoma models in vitro, and should be further investigated in pre-clinical models.

U2 - 10.17635/lancaster/thesis/2529

DO - 10.17635/lancaster/thesis/2529

M3 - Master's Thesis

PB - Lancaster University

ER -