Alex Laird

Project Title

Molecular Profiling of Renal Cell Carcinoma

Supervisors

Professor Richard Meehan and Professor David Harrison

Funding

MRC (SCP3) Clinical Research Fellowship; The Melville Trust for the Care and Cure of Cancer and RCSEd Robertson's Trust Clinical Research Fellowship

Project Summary

Renal cell cancer (RCC) accounts for 2.5% of all adult cancers and 2.4% of all cancer deaths in Scotland, and it is the most deadly of all urological malignancies. There has been a 27% increase in incidence in RCC in Scotland over the last 10 years, in part due to the wider application of diagnostic imaging techniques resulting in more incidental tumours being identified. One third of RCC patients present with metastatic disease with a further 30-40% eventually developing distant metastases.

Metastatic RCC (mRCC) is uniquely resistant to both chemotherapy and radiotherapy. Adjuvant treatment has traditionally been in the form of immunotherapy with interleukin-2 and interferon-α. Robust studies determined that patients presenting with metastatic RCC benefited from cytoreductive nephrectomy followed by immunotherapy compared with immunotherapy alone. However immunotherapy has substantial toxicity and limited efficacy with response rates of, 6% for interleukin-2 and 10-20% for interferon-α. As a result there has been a shift from cytokine based to more targeted therapies which have been shown an approximate doubling of the progression free survival compared to immunotherapy treated controls, with acceptable side-effect profiles. Of the currently available targeted therapies, sorafenib, sunitinib, temsirolimus and pazopanib have been approved in the EU and US.

Despite the advances in diagnosis and management of RCC, there has been little progress made in predicting which patients will relapse following extirpative surgery and subsequently who will respond to targeted therapy in the metastatic setting. We propose that systematic proteomic, transcriptomic, genetic and epigenetic (methylation) analysis of primary and metastatic RCC tissue before and after treatment with tyrosine kinase inhibitors will allow us to understand tumour biology and develop prognostic and predictive biomarkers.