The number of cases of kidney cancer diagnosed in the UK, and in many other industrialised countries, has doubled in the past thirty years. Almost half of all patients diagnosed with kidney cancer die from the disease. We urgently need to improve treatment for patients with kidney cancer.
Pictured left is Ms Shie-Hong Chang, a MKF-funded Ph.D. student in the p53/MDM2 Research Group at the University of Liverpool Cancer Research Centre, 200 London Road, Liverpool L3 9TA. Shie-Hong is currently writing up her thesis having completed her laboratory research.
One of the major factors determining whether a patient will die from kidney cancer is whether the disease spreads away from the primary tumour to new sites in the body, a process known as metastasis. As with many types of cancer, some small tumours metastasise early and yet some large tumours never do. We are investigating mechanisms that determine this difference with the aim of identifying better approaches for therapy that would target the molecular basis of these differences (Noon et al., 2010). Our studies rely partly on the understanding we have developed of the unusual way that the kidney responds to chemotherapeutic drugs (reviewed in (Vlatkovic et al., 2011)).
We have focussed on a protein called MDM2 that promotes kidney cancer, in part through an interaction with a protein called p53, a cancer suppressing protein known as the “guardian of the genome”. We have found that MDM2 function is abnormal in kidney cancer cells (Warburton et al., 2005) and increased amounts of MDM2 are linked with more aggressive kidney tumours (Noon et al., 2012), typically together with abnormally high levels of normal p53 protein which in other cancers helps to prevent disease, but which seems to fail to do so in kidney cells. Indeed, as we showed in studies we published in 2012, analysis of MDM2 and p53 provides a promising way to predict how an individual patient’s disease will progress.Our current research is aimed at testing the hypothesis that MDM2 promotes more aggressive behaviour in renal cancer cells and that the balance between MDM2 and other proteins it interacts with particularly p53, determines tumour aggressiveness (we will also study another protein we discovered to be involved in this process which suppresses metastasis called NME). Future work will be aimed at screening for potential therapeutic compounds to inhibit interactions between MDM2 and other proteins such as p53.
Noon, A.P., Polanski, R., El-Fert, A.Y., Kalirai, H., Shawki, H., Campbell, F., Dodson, A., Eccles, R.M., Lloyd, B.H., Sibson, D.R., et al. (2012). Combined p53 and MDM2 biomarker analysis shows a unique pattern of expression associated with poor prognosis in patients with renal cell carcinoma undergoing radical nephrectomy. BJU Int 109, 1250-1257.
Noon, A.P., Vlatkovic, N., Polanski, R., Maguire, M., Shawki, H., Parsons, K., and Boyd, M.T. (2010). p53 and MDM2 in renal cell carcinoma: biomarkers for disease progression and future therapeutic targets? Cancer 116, 780-790.
Polanski, R., Maguire, M., Nield, P.C., Jenkins, R.E., Park, B.K., Krawczynska, K., Devling, T., Ray-Sinha, A., Rubbi, C.P., Vlatkovic, N., et al. (2011). MDM2 interacts with NME2 (non-metastatic cells 2, protein) and suppresses the ability of NME2 to negatively regulate cell motility. Carcinogenesis 32, 1133-1142.
Polanski, R., Warburton, H.E., Ray-Sinha, A., Devling, T., Pakula, H., Rubbi, C.P., Vlatkovic, N., and Boyd, M.T. (2010). MDM2 promotes cell motility and invasiveness through a RING-finger independent mechanism. FEBS Lett 584, 4695-4702.
Vlatkovic, N., Crawford, K., Rubbi, C.P., and Boyd, M.T. (2011). Tissue-specific therapeutic targeting of p53 in cancer: one size does not fit all. Curr Pharm Des 17, 618-630.
Warburton, H.E., Brady, M., Vlatkovic, N., Linehan, W.M., Parsons, K., and Boyd, M.T. (2005). p53 regulation and function in renal cell carcinoma. Cancer Res 65, 6498-6503.
Figure 1. Analysis of patient survival for a cohort of patients with kidney cancer analysed by standard clinical staging and by p53/MDM2 levels shows that both approaches distinguish patients with differing responses to treatment (reproduced from Noon et al., The British Journal of Urology international, 2012)