Brain Cancer @ Leeds

Radiation Biology and Therapy

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Research Overview

We are investigating mechanisms of radiation resistance in glioma and its association with the stem cell phenotype. We are researching novel ways of radio-sensitising tumours, particularly through inhibiting DNA repair. The main focus of this work falls into three areas:

This lab work complements a portfolio of clinical studies for patients with glioma with a focus on novel adjuvant treatments for poor prognosis sub-types

Inhibiting homologous recombination
We have recently shown that the double-strand break repair protein Rad51 is highly expressed in glioma stem cells and that these cells are highly reliant on Rad51 dependent repair following radiation. Using tool compounds as inhibitors we also demonstrated radiosensitisation and loss of the SOX2 positive, stem cell population after combined treatment. Since no clinical agents are available to directly target this pathway we are investigating whether heat-shock protein (HSP) inhibition may be an alternative approach since Rad51 and related HR proteins are HSP clients.

Targeting stem cell maintenance pathways
A plethora of pathways are known to contribute to maintaining the stem cell phenotype in glioma and several of these have multiple effects on aspects of stem cell biology including proliferation, migration and differentiation status. We are investigating whether targeting the GSK3-beta pathway, upstream of wnt-beta catenin signaling may be an effective way of reversing malignant aspects of the stem cell phenotype and/or affecting sensitivity to radiation.

Promoting immunogenic cell death after radiation
Enhancing the local immune response in glioma is recognized as an important objective that may improve treatment outcome, especially following radiation treatment, which promotes potentially immunogenic cell death. We are investigating the use of immunotherapies including oncolytic viruses as adjuvants to radiation in glioma models. In parallel we are investigating the utility of using OV as delivery vehicles for constructs including micro-RNAs, that may enhance cytotoxicity of radiation.

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