Exploring the Potential use of TEAD Inhibition as Part of a Combination Therapy for NF2-Deficient Schwannoma and Meningioma.

NF2-related Schwannomatosis is a genetic cancer predisposition syndrome, resulting in the development of schwannoma, meningioma and ependymoma tumours. Although surgical resection and adjuvant radiotherapy can be used, new avenues of therapeutic development are essential to target inoperable and recurrent tumours. Previous studies evaluating small molecule TEAD auto-palmitoylation inhibitors have distinguished their anti-proliferative effect in NF2-deficient cancers. Here we aim to identify compounds that could be utilised in conjunction with TEAD inhibition, to target aberrant Hippo signalling and secondary resistance mechanisms. We utilised immortalised and primary cells to evaluate the efficacy and potential synergism of TEAD inhibitors VT3989 and VT107 in combination with brigatinib. Further preclinical in vivo modelling was used, including pre-established intracranial meningioma xenograft implantations and the Postn-Cre;Nf2 fl/fl schwannoma mouse model. These efforts determined that the VT3989/brigatinib combination demonstrates synergistic inhibition of cell viability in meningioma and schwannoma cells, while supressing tumour growth and proliferation of NF2-deficient meningioma xenografts, and the spontaneous schwannoma model. Furthermore, in the absence of ALK, it was determined that the VT3989/brigatinib combination treatment interacts with various tyrosine kinases, alongside a reduction in TEAD driven transcriptional activity to induce its anti-neoplastic effect. Due to the broad inhibitory profile and off target effects of brigatinib, alternative pre-established inhibitors pictilisib and selumetinib were evaluated, reducing proliferation and cell viability of NF2-deficient cells. This thesis had provided evidence that pharmacological disruption of TEAD transcription as part of a combinational strategy demonstrates a major advancement in the development of therapeutics for NF2-related Schwannomatosis.

Author dc:creator

• Blake, Jamie

Contributors dc:contributor

• Liyam Laraba, Juri Na, David Parkinson

Language dc:language

eng

Repository record dc:identifier

https://pearl.plymouth.ac.uk/pms-theses/67

OAI identifier oai:identifier

oai:pearl.plymouth.ac.uk:pms-theses-1066