Hypoxia, regulatory T cells and the DNA damage response in canine cancer

Supervisors: 

Professor Oliver Garden (ogarden@rvc.ac.uk ),  Dr Henny Martineau (hmartineau@rvc.ac.uk ), Dr Ester Hammond  Department of Oncology, University of Oxford (ester.hammond@oncology.ox.ac.uk )

Solid tumours are characterised by regional hypoxia. Induction of hypoxia-inducible factor (HIF)-1α  promotes the accumulation of regulatory T cells (Tregs), which inhibit the anti-neoplastic immune response. Activation of a DNA damage response (DDR) occurs in areas of marked hypoxia. Sensitisation of tumour cells to fluxes in oxygen tension by inhibition of HIF-1a and DDR proteins may represent a novel therapeutic strategy, overcoming the chemo- and radio-resistance of hypoxic cells.

Dogs suffer from a variety of cancers that model those of humans. Little is known about the role of hypoxia and the DDR in canine cancer. We hypothesise that canine tumours are characterised by regions of hypoxia associated with perturbations of the local microenvironment, which include the up-regulation of HIF-1a – with the parallel accumulation of Tregs – and a DDR. We will obtain biopsy specimens from tumours of epithelial, mesenchymal and round cell origin  from a canine cancer archive, undertaking immunohistochemistry for key HIF-1a target molecules; FOXP3 (Tregs); H2AX and/or 53BP1 (DDR markers); and Rad51, ATM and/or p53 (DDR repair molecules). Using an image analysis platform, we will correlate the expression of these markers with those of hypoxia, making comparisons to non-neoplastic control tissues.

We would welcome informal approaches by students interested in this exciting project, which builds upon encouraging preliminary data currently being submitted for publication.  Representing an evolving collaboration between the RVC and University of Oxford, we aim to publish this work. Please direct enquiries to ogarden@rvc.ac.uk in the first instance.  

References

1. Tang CM and Yu J (2013) Hypoxia-inducible factor-1 as a therapeutic target in cancer. J Gastroenterol Hepatol 28: 401-405.

2. Hammond EM, Kaufmann MR and Giaccia AJ (2007) Oxygen sensing and the DNA-damage response. Curr Opin Cell Biol 19: 680-684.

3. Paoloni M and Khanna C (2008) Translation of new cancer treatments from pet dogs to humans. Nat Rev Cancer 8: 147-156.

If you would like to apply for this studentship please contact the supervisors in the first instance and then apply via UKPASS. See also the How to Apply box

The deadline for applications is 3rd April 2016