Targeting mtTERT promoter for treatment of GBM
Glioblastoma (GBM) is a grade IV astrocytoma responsible for nearly 17,000 deaths every year. The current median survival time for GBM patients is just 14 months after surgical debulking and standard of care (Radiation + Temozolomide), suggesting that new treatment options are a clinically unmet need for GBM patients. Approximately 86% of GBM tumors exhibit mutation at -124 or -146 bases upstream of the ATG start site in the transcription activating promoter region of Human telomerase reverse transcriptase (hTERT). Mutation in the promoter region of hTERT leads to overexpression of hTERT; inappropriate hTERT is associated with oncogenesis, tumor maintenance, and resistance to apoptosis. A small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC260, has been developed that restores the wild-type tertiary structure of hTERT promoter. In this work we investigate efficacy of GTC260 in shortening telomere length in selected long-term established glioma cell lines harboring mutant hTERT promoter (T98G, U87, SNB19, A172) and immortalized normal glial cell line with wild type hTERT promoter (SVG) using quantitative PCR (qPCR) assay. hTERT is a catalytic subunit of the enzyme telomerase and is crucial to the regulation of telomere maintenance, however, some literature suggests that it may also exhibit non-telomere lengthening roles in cancer. To that end we investigated subcellular localization of hTERT protein in glioma cells using western blot and showed significantly higher expression of hTERT in cytoplasm as compared to nucleus, suggesting hTERT may be playing a non-canonical role in glioma pathogenesis. In summary, our data suggest that canonical and non-canonical functions of hTERT in glioma pathogenesis need to be investigated in more detail to identify the context of vulnerability to hTERT inhibition.