University of Cambridge
Developing Novel Models and Therapeutics for ZFTA-RELA Ependymoma
Abstract
dc:description.abstractPaediatric brain tumours are the leading cause of cancer related death in children. Ependymomas are the third most common brain tumour in children. These tumours are found to be incurable in 40% of cases, in large part because of a lack on new treatments. Thirty percent of all ependymomas occur in the supratentorial region, of which 70% are by chromothripsis of chromosome 11q that results in a gene translocation between the Zinc Finger Translocation Associated (ZFTA) gene and V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A (RELA), the principal effector of NF-KB signalling. ZFTA-RELA fusion ependymomas are recognised by the World Health Organisation (WHO) classification of CNS tumours as a distinct disease entity with an especially poor prognosis. Although genetically modified mouse models (GEMM) of cancers are useful for understanding the biology and treatment of cancer, no GEMMs of ependymoma have been generated: current models require invasive intracranial injection of cells or gene constructs during embryogenesis. This thesis describes research to generate and characterise novel GEMMs of ZFTA-RELA ependymoma as well as the development of candidate compounds as new treatments of this disease. Here, we describe the first GEMMs of ZFTA-RELA ependymoma and their clinical, histological, transcriptomic and proteomic characteristics. This work revealed the unique susceptibility of intracranial neural progenitors to oncogenic transformation by ZFTA-RELA and stalled lineage differentiation that underpins their development. Despite induction of gene recombination in our GEMMs, histological evidence of tumourigenesis was not apparent until the post-natal period, implicating additional events including differentiation crisis and epigenomic regulation in transformation. In further work, we increased the repertoire of pre-clinical models using allografting to increase utilisation in pre-clinical studies. These models responded to conventional standard of care therapeutic modalities, providing a resource for further work. Screening of large numbers of candidate compounds enabled selection of molecules including a CLK2 inhibitor as potential therapies for further development, highlighting gene splicing as a potential therapeutic vulnerability of ZFTA-RELA ependymomas. This work provides insights into the initiation and progression of a ZFTA-RELA ependymoma, while providing transcriptomic and proteomic resources to be further investigated.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2024
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Bonner, Sigourney
- Advisor dc:contributor.advisor
-
- Gilbertson, Richard
Subjects
dc:subject × 4Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.114555
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/377875