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Exploring mechanisms of resistance to anti-angiogenic therapy in breast cancer

  • Full or part time

    Prof N Brown
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Vascular endothelial growth factor (VEGF) is a potent angiogenesis inducer and is often overexpressed in cancer. Circulating levels of VEGF as well as tumour microvessel density are of prognostic value in breast cancer. VEGF pathway inhibitors are now used in the clinic, and/or are being tested in breast cancer clinical trials. However, despite substantial progress in this area, the overall benefits of anti-angiogenic therapies are modest and even initially responsive patients eventually develop resistance. Further advancement in this field is therefore reliant on identifying mechanisms of resistance that can be targeted to improve patient outcomes.

The project will investigate the role of the small heat shock protein B-crystallin for its potential contribution to resistance to VEGF pathway inhibitors in breast cancer. B-crystallin is encoded by the CRYAB gene and is often overexpressed in triple negative breast cancer and basal breast cancer, which are the most aggressive forms of the disease. B-crystallin functions as a “chaperone” to protect misfolded proteins including VEGF from degradation and as such it is considered to be a key regulator of angiogenesis. High levels of tumour B-crystallin were found to correlate with invasion and metastasis, poor survival and chemotherapy resistance. Here we hypothesise that B-crystallin overexpression is a key determinant of resistance to VEGF pathway inhibitors in breast cancer.

The main aims of this project are to a) establish a panel of breast cancer cell lines expressing different levels of B-crystallin using molecular techniques including CRISPR/Cas9 nickase gene editing and overexpression and b) use the cell lines developed in in vitro and in vivo models to assess the consequences of altered B-crystallin levels on breast cancer cell survival, invasive potential and response to VEGF pathway inhibition.

Successful results of this study will be of translational relevance and could lead to the development of therapeutic strategies aimed at targeting B-crystallin and VEGF interactions.

Funding Notes

Eligibility:

Candidates must have a First Class or Upper Second Class Honors Degree (or equivalent) in a Biological Sciences related subject. In addition, candidates are expected to be proficient in English.

References

How to apply

For initial enquiries please contact Dr Chryso Kanthou (Tel: +44 114 215 9052; email: [email protected]).

To apply, please complete a University Postgraduate Research Application form (https://www.sheffield.ac.uk/postgraduate/research/apply/applying) clearly stating the prospective main supervisor in the respective box and select 'Oncology & Metabolism' as the Department.

Related Subjects

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