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Novel Target Discovery and Validation in Renal Cell Carcinoma

Trainor, Sebastian (2018) Novel Target Discovery and Validation in Renal Cell Carcinoma. PhD thesis, University of Leeds.

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Abstract

Renal cell carcinoma (RCC) is the 7th most common cancer in the UK. Almost one third of patients will have locally advanced or metastatic disease at presentation and a similar proportion will relapse despite undergoing surgery with a curative intent. More effective treatments are now available, although resistance is typically observed within months of starting treatment and median survival remains in the order of two years, highlighting the need for continued progress. The aim of this work was the discovery and further investigation of novel therapeutic targets in ccRCC through proteomic approaches. Two potential emerging targets were further investigated in ccRCC. Spleen tyrosine kinase (SYK) was identified to be alternatively spliced in ccRCC compared to normal tissue. SYK inhibition with R406 caused cell death at concentrations >1 μM. Transient Receptor Potential Canonical (TRPC) channels 1, 4 and 5 expression was variable at an mRNA level in primary ccRCC and normal kidney tissue but the lack of antibodies to accurately detect the TRPC proteins using Western blot limited detection at a protein level. The activation and inhibition of these channels in-vitro was explored in the A498 RCC cell line. A comprehensive proteomic analysis of ccRCC tissue compared with normal kidney tissue, selected on the basis of underlying genomic changes was undertaken. Integration of the data led to the identification of a number of potential novel therapeutic targets. Cyclooxygenase-1 (COX-1) and proteasome subunit type beta-9 (PSMB9), were taken forward and their upregulation in ccRCC at a protein level were demonstrated. Inhibition of COX-q was shown to cause RCC cell line death. The genetics of RCC at a descriptive level is comprehensive, but has not yet led to advances in treatment options. This work has demonstrated a valid approach to the integration of genomic and proteomic data that may be adopted in future studies.

Item Type: Thesis (PhD)
Keywords: Renal Cell Carcinoma, ccRCC, Spleen tyrosine kinase, SYK, Transient Receptor Canonical Potential channels, TRPC, proteomic, discovery
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds)
Identification Number/EthosID: uk.bl.ethos.773976
Depositing User: Mr Sebastian Trainor
Date Deposited: 15 May 2019 11:10
Last Modified: 18 Feb 2020 12:50
URI: http://etheses.whiterose.ac.uk/id/eprint/23860

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