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Lookup NU author(s): Professor Gareth Veal, Philip Berry
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.Background: There is increased pan-cancer specific interest in repurposing the poly adenosine diphosphate-ribose polymerase-1 (PARP-1) inhibitor, olaparib, for newly diagnosed or recurrent isocitrate dehydrogenase wild type glioblastoma. We explore whether intra-cavity delivery of olaparib confers a survival benefit in a pre-clinical high-grade glioma model. Methods: Primary tumor RNA sequencing data was used to determine PARP-1 as a target in the glioblastoma infiltrative margin. We assessed radiosensitization conferred by olaparib alone and concomitant to genotoxic insults in vitro using clonal growth assays, cell cycle analysis and immunocytochemistry, and in vivo upon post-surgical delivery from a temperature-sensitive polymeric paste. Results: RNA-sequencing confirmed PARP-1 as a viable therapy target in glioblastoma infiltrative disease. Acute exposure of glioma cells to olaparib impaired proliferation and induced late-stage apoptosis associated with DNA damage in vitro, potentiated by radiation. Using high-grade glioma orthotopic allografts, a long-term overall survival benefit was observed upon interstitial olaparib delivery concomitant with radiotherapy, compared to systemic olaparib and standard glioblastoma treatment. Combined delivery of olaparib with either temozolomide or etoposide increased long-term survival, suggestive of olaparib functioning as DNA damage sensitizer. Conclusions: Collectively, our data support a rationale for localized olaparib delivery concomitant with the current clinical regimen for malignant glioma treatment.
Author(s): Serra R, Smith SJ, Rowlinson J, Gorelick N, Moloney C, McCrorie P, Veal GJ, Berry P, Chalmers AJ, Suk I, Shakesheff KM, Alexander C, Grundy RG, Brem H, Tyler BM, Rahman R
Publication type: Article
Publication status: Published
Journal: British Journal of Cancer
Year: 2024
Pages: epub ahead of print
Online publication date: 22/10/2024
Acceptance date: 04/10/2024
Date deposited: 06/11/2024
ISSN (print): 0007-0920
ISSN (electronic): 1532-1827
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41416-024-02878-2
DOI: 10.1038/s41416-024-02878-2
Data Access Statement: Raw RNA-seq data for spatially distinct unsorted GBM regions and 5ALA fluorescence activated cell sorted cells have been deposited at the ArrayExpress with accession number: EMTAB-8743. All other data are available in the main text or supplementary materials.
PubMed id: 39433869
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