Project description
Pioneering targeted therapy to disrupt DNA repair in glioblastoma cells
Glioblastoma is a fast-growing and aggressive form of brain cancer. There are an estimated 250 000 new cases worldwide each year, of which only a small fraction of patients survive beyond five years. Standard treatment involves surgical removal of the tumour, followed by radiation and oral chemotherapy with Temozolomide (TMZ) to eradicate the cancer cells. Unfortunately, the cancer cells quickly build up therapy resistance owing to DNA repair mechanisms. This strongly suggests that targeted therapy could prove more effective. Through a multidisciplinary approach, the ERC-funded TrapKill project aims to develop a novel therapeutic trifunctionalised hydrogel that will disrupt DNA repair mechanisms in the cancer cells, thus increasing their vulnerability to radiotherapy and TMZ chemotherapy.
Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences genetics RNA transcriptomes
- medical and health sciences clinical medicine oncology
- engineering and technology industrial biotechnology biomaterials
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
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(opens in new window) ERC-2024-STG
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H91 Galway
Ireland
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