Development and Optimisation of Tumour Treating Fields (TTFields) Delivery within 3D Primary Glioma Stem Cell-like Models of Spatial Heterogeneity.

Simple Summary: Glioblastomas are aggressive and therapy-resistant high-grade brain tumours that cause around 200,000 worldwide deaths each year. Tumour Treating Fields (TTFields) therapy represents an important advance in the management of glioblastomas, providing ~five months of survival, which has led to clinical approval in multiple countries worldwide. However, even with this, only around 13% of patients with a newly diagnosed glioblastoma survive more than five years. As such, there is an urgent need to improve our understanding of the cellular responses to TTFields in the context of clinically relevant glioblastoma models and identify new treatment regimens that could augment the effectiveness of TTFields. In this manuscript, we report the development and optimization of a new 3D glioma stem cell model system that facilitates the assessment of TTFields therapies alongside chemoradiotherapy and approved/emerging new therapeutics. This, therefore, provides a key preclinical platform for the development of new TTFields-based approaches to improve the treatment of these currently incurable tumours. Glioblastoma is an aggressive, incurable brain cancer with poor five-year survival rates of around 13% despite multimodal treatment with surgery, DNA-damaging chemoradiotherapy and the recent addition of Tumour Treating Fields (TTFields). As such, there is an urgent need to improve our current understanding of cellular responses to TTFields using more clinically and surgically relevant models, which reflect the profound spatial heterogeneity within glioblastoma, and leverage these biological insights to inform the rational design of more effective therapeutic strategies incorporating TTFields. We have recently reported the use of preclinical TTFields using the inovitroTM system within 2D glioma stem-like cell (GSC) models and demonstrated significant cytotoxicity enhancement when co-applied with a range of therapeutically approved and preclinical DNA damage response inhibitors (DDRi) and chemoradiotherapy. Here we report the development and optimisation of preclinical TTFields delivery within more clinically relevant 3D scaffold-based primary GSC models of spatial heterogeneity, and highlight some initial enhancement of TTFields potency with temozolomide and clinically approved PARP inhibitors (PARPi). These studies, therefore, represent an important platform for further preclinical assessment of TTFields-based therapeutic strategies within clinically relevant 3D GSC models, aimed towards accelerating clinical trial implementation and the ultimate goal of improving the persistently dire survival rates for these patients. [ABSTRACT FROM AUTHOR]