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Biological significance, predictive value and targeting of the HER family members in pancreatic cancer

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  • Full or part time
    Prof H Modjtahedi
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Despite major advances in imaging technologies, surgery, chemotherapy, radiotherapy and targeted therapy of cancer in the last few decades, pancreatic cancer remains as one of the most aggressive and fatal types of human cancer. It is the only type of cancer which has an annual mortality rate which nearly equals its annual incidence rate. Therefore, it is of prime importance to discover not only more specific therapeutic targets but also to identify those factors which are responsible for the poor response or development of resistance to therapies in patients with pancreatic cancer.

Since the early 1980s, aberrant expression and activation of the human epidermal growth factor receptor (also called EGFR, HER, erbB) system has been reported in a wide range of human epithelial malignancies, including pancreatic cancer (1). In some studies, the expression of some member of the HER family, in particular EGFR and HER-2, have also been associated with a poor prognosis and resistance to conventional therapies (1). These discoveries have led to the strategic development and approval of several anti-EGFR monoclonal antibodies and small molecule EGFR tyrosine kinase inhibitors (TKIs) for the treatment of a wide range of human cancers. However, of the HER inhibitors, only the EGFR TKI erlotinib was approved for the treatment of patients with pancreatic cancer but the duration of response is short (i.e. 11 days). Moreover, the underlying mechanisms of primary and secondary resistance to HER inhibitors in pancreatic cancer remain unclear (1-4).

The aims of this PhD project are to determine the biological significance and predictive value of EGFR family members, their ligands, and other growth factor receptors for response to treatment various types of targeting agents in pancreatic cancer. We shall use a wide range of techniques in this study including; Cell Culture, Cell growth study in 2D and 3D models, Flow Cytometry, Western Blotting, Proteome Phospho-Receptor Tyrosine kinase array, Migration and Invasion assays, and immunohistochemistry. All these techniques are used routinely in our laboratories and some of them can be found in our list of selected publications (1-4).

Funding Notes

There is no funding for this project: applications can only be accepted from self-funded candidates

References

1. Ioannou N, Seddon A, Dalgleish A, Mackintosh D and Modjtahedi H (2012). Expression pattern and targeting of targeting of HER family members and IGF-IR in pancreatic cancer. Frontiers in Bioscience 17:2698-724.

2. Ioannou N, Seddon AM, Dalgleish A2, Mackintosh D, Solca F, and Modjtahedi H (2016). Acquired resistance of pancreatic cancer cells to treatment with gemcitabine and HER-inhibitors is accompanied by increased sensitivity to STAT3 inhibition. International Journal of Oncology 48(3), 908-918.

3. Ioannou I, Seddon AM, Dalgleish A, Mackintosh D and Modjtahedi H (2013). Treatment with a combination of the ErbB (HER) family blocker afatinib and the IGF-IR inhibitor, NVP-AEW541 induces synergistic growth inhibition of human pancreatic cancer cells. BMC Cancer 31;13:4. doi: 10.1186/1471-2407-13-41.

4. Ioannou N, Dalgleish A G, Seddon A M, Mackintosh D, Guertler U, Solca F and Modjtahedi H (2011) Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells. British Journal of Cancer 105:1554–1562.

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