Trapping and Killing Glioblastoma

Introduction

Glioblastoma Multiforme (GB) is an aggressive brain cancer associated with a 2% 5-year survival rate and 250,000 new diagnoses globally. Gold standard treatment includes surgical resection and radiotherapy coupled with Temozolomide (TMZ) chemotherapy that promotes cancer cell death. Resistance to TMZ and radiotherapy develops rapidly due to DNA repair mechanisms, indicating that targeted disruption of them can potentiate these therapies.

Project Overview

TrapKill combines cancer mechanobiology, microfabrication, and biomaterials engineering to develop a pioneering therapeutic trifunctionalised hydrogel, physically modified to present 3D microchannels, and chemically functionalised with GB chemoattractant CXCL-12 and TMZ. These promote durotaxis/chemotaxis-mediated GB cell infiltration, constraining cells into elongated morphologies, stressing the nucleus, disrupting DNA repair mechanisms, and rendering cells susceptible to therapies.

Preliminary Findings

I have shown that 3D patterned hydrogels promote GB GL261 cell infiltration, forcing cells to adopt a filamentous conformation and subjecting the cell nuclei to significant shear/tension/compressive forces. Following microchannel sequestering, preliminary data indicate that cells upregulate stress-related signalling processes and lose the protective effects of cell agglomeration. It is envisaged that TrapKill glioblastoma therapy will significantly enhance the efficacy of gold standard chemo-radio-therapy approaches.

Objectives

TrapKill objectives include:

1. A chemoattractant-TMZ functionalised and micropatterned hydrogel to create TrapKill therapy.
2. Analysis of microchannel dimensions on GB cell morphology, nuclear stress, and cell sensitivity to TMZ/gamma radiation in vitro.
3. Assess transcriptome changes in mechanically stressed GB cells and in DNA repair gene transcription.
4. Pre-clinical resection-radiation murine GB model assessment.

Conclusion

TrapKill will create a transformative GB treatment, with a combined approach to significantly revolutionise existing/next-generation GB therapies.