Rominiyi, O. orcid.org/0000-0002-9724-0224 and Collis, S.J. orcid.org/0000-0002-7874-1891 (2022) DDRugging glioblastoma: understanding and targeting the DNA damage response to improve future therapies. Molecular Oncology, 16 (1). pp. 11-41. ISSN 1574-7891
Abstract
Glioblastoma is the most frequently diagnosed type of primary brain tumour in adults. These aggressive tumours are characterised by inherent treatment resistance and disease progression, contributing to ~190,000 brain-tumour related deaths globally each year. Current therapeutic interventions consist of surgical resection followed by radiotherapy and temozolomide chemotherapy, but average survival is typically around 1 year, with less than 10% of patients surviving more than 5 years. Recently, a fourth treatment modality of intermediate-frequency low-intensity electric fields [called tumour-treating fields ( TTFields)] was clinically approved for glioblastoma in some countries after it was found to increase median overall survival rates by ~5 months in a phase III randomised clinical trial. However, beyond these treatments, attempts to establish more effective therapies have yielded little improvement in survival for patients over the last 50 years. This is in contrast to many other types of cancer and highlights glioblastoma as a recognised tumour of unmet clinical need. Previous work has revealed that glioblastomas contain stem-cell-like subpopulations that exhibit heightened expression of DNA damage response (DDR) factors, contributing to therapy resistance and disease relapse. Given that radiotherapy, chemotherapy and TTFields-based therapies all impact DDR mechanisms, this Review will focus on our current knowledge of the role of the DDR in glioblastoma biology and treatment. We also discuss the potential of effective multi-modal targeting of the DDR combined with standard-of-care therapies, as well as emerging therapeutic targets, in providing much-needed improvements in survival rates for patients.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Chemotherapy; DNA damage response (DDR); Glioblastoma; Radiotherapy; Synthetic lethality; Tumour treating fields (TTFields) |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) |
Funding Information: | Funder Grant number ROYAL COLLEGE OF SURGEONS OF ENGLAND nan NOVOCURE LTD nan American Association For Cancer Research 833961 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 09 Jun 2021 15:44 |
Last Modified: | 21 Feb 2022 14:41 |
Status: | Published |
Publisher: | Wiley Open Access |
Refereed: | Yes |
Identification Number: | 10.1002/1878-0261.13020 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:174729 |