Objective
New treatment modalities are needed to augment present therapies for metastasising colorectal cancer. The TNF-related-apoptosis-inducing ligand (TRAIL; ApoL2) has been shown to specifically induce cell death in tumour cells, including colorectal cancer cel ls, leaving normal healthy tissue unaffected. Gene therapy approaches using TRAIL have the advantage over bolus injections of recombinant protein, that the cytokine can continuously exert its anti-tumour effect. However, clinical gene therapy applications have been hampered by a combination of side effects and poor delivery. One way to overcome this hurdle is to utilise the functions of stem cells drawn upon by the growing tumour, i.e. tumours require formation of supportive mesenchymal stroma and exogenously delivered mesenchymal stem cells (MSC) preferentially engraft at the tumour sites and contribute to the population of stromal fibroblasts.
Our goal is to transduce MSCs with an expression construct carrying an engineered, secreted version of TRAIL. The MSCs will be transduced ex vivo with Adeno-associated viral (AAV) vectors that are known to facilitate long-term gene expression and trigger no substantial immune responses. The AAV vectors will be optimised for the transduction of MSC by the use of bi-specific antibodies and a bio-selection procedure.
This procedure aims to isolate mutants that show improved transduction of MSC. Finally the TRAIL-loaded MSC will be tested in various colon cancer models for efficacy and safety. In summary we will engineer a combined cell-gene therapy system combining the safety features of AAV and TRAIL and the tumour-delivery potential of MSCs, which we will further enhance by chemokine-guided recruitment to the tumour. In order to reach our goal of combating colon cancer u sing adult stem cells and modern vector technology, I wish to build an international research team at the National University of Ireland, Galway.
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.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesclinical medicineoncologylung cancer
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesclinical medicineoncologycolorectal cancer
- medical and health sciencesclinical medicineoncologypancreatic cancer
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Keywords
Call for proposal
FP6-2005-MOBILITY-8
See other projects for this call
Funding Scheme
EXT - Marie Curie actions-Grants for Excellent TeamsCoordinator
GALWAY
Ireland