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Harnessing of hematopoietic stem cells for targeting of brain metastases

Objective

Brain metastases occur in 20 to 35% of cancer patients and are associated with poor prognosis due to the lack of efficient treatments. Targeting of brain lesions poses several challenges including the poor penetration of drugs into the brain due to the tightness of the blood-brain barrier. Therefore improved approaches for the delivery of therapeutic agents to brain lesions are urgently required.
The goal of this project is to develop a cell-based strategy to deliver therapeutic agents to brain metastases. This will be achieved by stable introduction of genes encoding secreted therapeutic molecules with anti-cancer properties into hematopoietic stem cells (HSCs). Upon transplantation, the progeny of HSCs will home to cancer lesions, thereby delivering the therapeutic agent of choice.
We already demonstrated that the progeny of genetically engineered HSCs readily crosses the blood-brain barrier and homes to brain metastases in animal models where it efficiently expresses the delivered gene. Here we aim to further improve our approach in pre-clinical models to facilitate its clinical translation. To this end we aim to improve the efficiency of therapeutic delivery by increasing the infiltration of HSC progeny into the brain via whole brain radiation, a standard therapy for brain metastases. Secondly, we aim to improve the specificity of therapeutic delivery by identification of gene promoters that are active specifically within HSC progeny infiltrating the tumour. Expression of therapeutic agents by these promoters will restrict their delivery to tumour lesions. Thirdly, we aim to demonstrate a therapeutic efficacy of HSC-based drug delivery in combination with an enzyme / prodrug approach.
Due to the advanced application of HSC transplantation and HSC-based cell therapies in the clinic, our approach has a strong potential for a successful clinical translation.

Call for proposal

FP7-PEOPLE-2011-CIG
See other projects for this call

Coordinator

UNIVERSITY OF LEEDS
Address
Woodhouse Lane
LS2 9JT Leeds
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 100 000
Administrative Contact
Martin Hamilton (Mr.)