| Project Overview: | Clear cell carcinoma is the commonest subtype of kidney cancer and typically harbours a somatic inactivating mutation of the Von Hippel Lindau (VHL) gene or methylation-mediated silencing of VHL as the defining carcinogenic alteration. Until recently, immunotherapy with gamma interferon or interleukin 2 were the only treatment options for metastatic kidney cancer. Both are associated with significant toxicities and a high failure rate. A phase III clinical trial of the mammalian target of rapamycin (mTOR) inhibitor everolimus has shown that it is highly effective in the treatment of clear cell kidney cancer and everolimus has subsequently been approved for the 2nd line therapy for metastatic kidney cancer. Despite these advances, 20% of patients who receive everolimus do not benefit and progress relentlessly and even those who respond initially develop resistance to therapy within 6-9 months of treatment.To date, our understanding of the molecular basis of primary and acquired everolimus resistance in kidney cancer is very limited and it is not possible to predict which individual patient will gain benefit from everolimus treatment. This has profound health economic implications, and treatment with this active agent is unlikely to be approved for use in the UK by NICE (National Institute for Clinical Excellence) until a predictive test for everolimus sensitivity is developed.The TCT laboratory has recently developed a functional gene signature that is predictive of response to Taxane based neo-adjuvant chemotherapy in primary breast cancer, using functional genomics siRNA screening data to identify genes that are predictive of drug response in human tumours before therapy exposure. Our aim is to use similar approaches in order to identify predictive biomarkers of everolimus response in kidney cancer through parallel analysis of gene expression in everolimus clinical trial tissues and whole genome RNA interference approaches to define genes functionally involved in everolimus sensitivity in kidney cancer cell lines. This project aims to identify predictive biomarkers of everolimus response in kidney cancer through a genomic siRNA screen. The genome will be screened in kidney tumour cell lines with and without drug treatment, differences in cell viability will indicate possible antagonistic or sensitizing genes. |
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| Screener: | Marco Gerlinger (Swanton Lab). Extension:3462, Rm 115 |
| Project Status: | Published |
| Publications: | Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target.. Gerlinger et al., 2012 |
| Project Start Date: | July 2009 |
| Keywords: | Everolimus Kidney cancer Viability |
| Hits: | NM_001042423 - MCT4 Identified to impair RCC cell viability. |
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