Improving and Personalising Treatment Options for Paediatric Brain Tumour Patients
Medulloblastoma (MB) is the most common form of paediatric brain tumour, representing 20 % of all paediatric intercranial tumours. Aggressive treatment protocols generally consisting of chemotherapy, radiation therapy and surgery are deployed to treat MB, yielding a 5-year overall survival rate of ~ 70 % for patients with average risk disease. However, radiation therapy is associated with high levels of toxicity and significant adverse effects, and long-term sequelae can be severe.
The use of genotoxic chemotherapy is of particular relevance for subsets of patients who have limited therapeutic options, and here a personalised approach to therapeutic decision-making would facilitate the stratification of patients and identify those likely to respond to chemotherapy, so that they could be spared unnecessary treatments and associated toxicities. Therefore, there is a need to identify molecular patterns that can reliably predict therapeutic responsiveness. Here, we have analysed the expression levels of 14 proteins involved in apoptosis signalling, both upstream and downstream of mitochondrial outer membrane permeabilization in MB cell lines, and found that a Principal Component Analysis approach could be used to identify the chemotherapeutic responsiveness of individual cell lines. When applied to patient mRNA data, we observed that this approach identified that a significant proportion of these patients were predicted to have chemosensitive disease, highlighting the potential that approaches such as these could have in stratifying patients for personalised treatment, and sparing them the toxicities associated with unnecessary treatment.
We also sought to determine anti-apoptotic dependencies of these cell lines that could be exploited to potentiate chemotherapy-induced cytotoxicity. Using BH3 profiling, we identified a dependence on the anti-apoptotic protein BCL-XL, and we confirmed that these cells can be sensitised to cisplatin treatment via BCL-XL knockdown, or using the BCL-XL inhibitor WEHI-539. However, WEHI-539 treatment alone does not induce cell death, and we have additionally identified a compensatory role for MCL-1 in protecting cells from WEHI-539 induced cell death. Combined inhibition of BCL-XL and MCL-1 results in extremely rapid induction of caspase-dependent apoptosis, and abolishes clonogenic survival.
In summary, our data shows for the first time that quantitative analysis of key apoptosis-related proteins can predict chemosensitivity in medulloblastoma cell lines, and provides rationale for further evaluation of dual inhibition of BCL-XL and MCL-1 in the treatment of medulloblastoma.
National Children's Research Centre (NCRC)
First SupervisorProf. Brona Murphy
Second SupervisorDr. Niamh Connolly
Third SupervisorDr. Philip O'Halloran
CommentsA thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2021
Published CitationFitzgerald M. Improving and Personalising Treatment Options for Paediatric Brain Tumour Patients. [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2021
- Doctor of Philosophy (PhD)
Date of award2021-11-30
- Doctor of Philosophy (PhD)