University of Cambridge
Novel Diagnostics and Therapeutic Approaches for Supratentorial Ependymoma
Abstract
dc:description.abstractEpendymoma is the third most common paediatric brain tumour. These tumours are incurable in up to 40% of cases. Previously classified as a single disease by histological criteria, ependymomas are now grouped into nine molecular subgroups, three in each compartment of the central nervous system. The largest subgroup of supratentorial ependymoma, initially identified by our lab in 2014, is characterised by a fusion of C11orf95 and RELA, or less commonly, YAP1. The C11orf95-RELA fusion protein acts as a potent driver of oncogenesis in mouse models, and patients with this form of the disease have a particularly poor prognosis. Here, I describe research to develop a new diagnostic antibody for C11orf95-RELA-fusion ependymoma as well novel therapeutic approaches to treat the disease. Antibodies raised against the C11orf95-RELA fusion epitope were selected through phage-display and tested in immunoblot and immunohistochemistry assays before lead immunoglobulins were subjected to affinity maturation via ribosome display. Affinity-matured candidates were assessed for their diagnostic potential in immunoblot analysis blotting, proteomic assays and immunohistochemistry on human and mouse tissue. Novel treatment approaches included the screening of chemical entities with known and unknown targets, with a novel PLK1 inhibitor being established for in vivo preclinical testing. Screens of FDA-approved drugs produced candidate drugs for repurposing. As these compounds display unfavourable blood-brain barrier penetrability, they were combined with a local delivery system. For this, a biodegradable hydrogel system was optimised and implemented into a multimodality treatment regimen for ependymoma mouse models. The release of a selection of compounds was tested in vitro and in vivo resulting in the selection of gemcitabine-loaded hydrogels as a novel treatment for preclinical efficacy studies. Collectively, this thesis presents approaches for facilitated diagnosis of fusion-positive tumours and present novel drug delivery systems and novel therapeutic compounds in a currently poorly treatable tumour.
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
- 2021
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Ruff, Lisa
- Advisor dc:contributor.advisor
-
- Gilbertson, Richard
Subjects
dc:subject × 5Rights
dc:rightsIdentifiers
dc:identifier.*- Author Identifier
- 0000-0001-7539-9472
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/322132