Telomerase inhibition is an effective therapeutic strategy in TERT promoter mutant-glioblastoma models with low tumor volume

Aquilanti, Elisa, Kageler, Lauren, Watson, Jacqueline, Baird, Duncan M ORCID: https://orcid.org/0000-0001-8408-5467, Jones, Rhiannon E, Hodges, Marie, Szegletes, Zsofia M, Doench, John G, Strathdee, Craig A, McFaline Figueroa, Jose Ricardo, Ligon, Keith, Beck, Matthew, Wen, Patrick Y and Meyerson, Matthew 2023. Telomerase inhibition is an effective therapeutic strategy in TERT promoter mutant-glioblastoma models with low tumor volume. Neuro-Oncology 25 (7) , pp. 1275-1285. 10.1093/neuonc/noad024

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Abstract

Background Glioblastoma is one of the most lethal forms of cancer, with 5-year survival rates of only 6%. Glioblastoma-targeted therapeutics have been challenging to develop due to significant inter- and intra-tumoral heterogeneity. Telomerase reverse transcriptase gene (TERT) promoter mutations are the most common known clonal oncogenic mutations in glioblastoma. Telomerase is therefore considered to be a promising therapeutic target against this tumor. However, an important limitation of this strategy is that cell death does not occur immediately after telomerase ablation, but rather after several cell divisions required to reach critically short telomeres. We, therefore, hypothesize that telomerase inhibition would only be effective in glioblastomas with low tumor burden. Methods We used CRISPR interference to knock down TERT expression in TERT promoter-mutant glioblastoma cell lines and patient-derived models. We then measured viability using serial proliferation assays. We also assessed for features of telomere crisis by measuring telomere length and chromatin bridge formation. Finally, we used a doxycycline-inducible CRISPR interference system to knock down TERT expression in vivo early and late in tumor development. Results Upon TERT inactivation, glioblastoma cells lose their proliferative ability over time and exhibit telomere shortening and chromatin bridge formation. In vivo, survival is only prolonged when TERT knockdown is induced shortly after tumor implantation, but not when the tumor burden is high. Conclusions Our results support the idea that telomerase inhibition would be most effective at treating glioblastomas with low tumor burden, for example in the adjuvant setting after surgical debulking and chemoradiation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	1522-8517
Date of First Compliant Deposit:	1 March 2023
Date of Acceptance:	24 January 2023
Last Modified:	25 Jan 2024 17:04
URI:	https://orca.cardiff.ac.uk/id/eprint/157417

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