Vardon, Ashley James;
(2023)
Cellular Senescence in paediatric diffuse high-grade glioma: from mechanism to therapeutic opportunities.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Paediatric-type Diffuse high-grade gliomas (PDHGGs) are aggressive brain tumours that are treated palliatively with radiotherapy. Radiation therapy can induce cellular senescence, a state where cells cease to divide, it can also create a therapeutic vulnerability in tumour cells. We investigated this hypothesis by combining in vitro and in vivo approaches with transcriptomics to understand the impact of radiation-induced senescence on PDHGGs and the vulnerability of these cells to senolytic agents. We found that radiation-induced senescence in PDHGGs creates a unique therapeutic opportunity that can be exploited using Navitoclax, a small molecule inhibitor of Bcl-2/ Bcl-xL. We demonstrated that Navitoclax in synergy with radiation induces cell death in PDHGGs both in vitro and in vivo, resulting in a significant improvement in survival in preclinical models. We further used single cell transcriptomic and immunohistochemical data identifying a distinct subpopulation of macrophages that are senescent and express high levels of senescence markers in human PDHGGs. To validate our findings, we utilised the p16-FDR mouse model combining with a K27M-driven glioma, GEMM that closely mimics human PDHGGs. Using this model, we identified further evidence of a sub-population of macrophage expressing a number of senescent markers. Overall, our study sheds light on the role of senescence in PDHGGs and presents a promising therapeutic strategy for this deadly cancer. Our integrated approach that combines preclinical models, transcriptomic data, and immunohistochemical analyses can provide a framework for targeting senescent cells in PDHGGs.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Cellular Senescence in paediatric diffuse high-grade glioma: from mechanism to therapeutic opportunities |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10174657 |
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