Trapping and Killing Glioblastoma

Descripción del proyecto

Tratamiento dirigido pionero para alterar la reparación del ADN en células de glioblastoma

El glioblastoma es un tipo de cáncer cerebral agresivo y de rápido crecimiento. Se calcula que cada año se producen 250 000 nuevos casos en todo el mundo, de los cuales solo una pequeña fracción de pacientes sobrevive más de 5 años. El tratamiento habitual consiste en la extirpación quirúrgica del tumor, seguida de radioterapia y quimioterapia oral con temozolomida (TMZ) para erradicar las células cancerosas. Por desgracia, las células cancerosas se vuelven rápidamente resistentes al tratamiento debido a los mecanismos de reparación del ADN. Esto sugiere que el tratamiento dirigido podría resultar más eficaz. Mediante un planteamiento multidisciplinario, el equipo del proyecto TrapKill, financiado por el Consejo Europeo de Investigación, pretende desarrollar un novedoso hidrogel terapéutico trifuncionalizado que altere los mecanismos de reparación del ADN en las células cancerosas, lo que aumentará su vulnerabilidad a la radioterapia y la quimioterapia con TMZ.

Objetivo

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 promote 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.

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. 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.

TrapKill objectives include:

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

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