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Identification of Novel Targeted Therapies for Renal Cancer

Final Report Summary - ONCOTREAT (Identification of Novel Targeted Therapies for Renal Cancer)

In this ERC-funded project we investigated how individuals might be predisposed to developing renal cell carcinoma (RCC) through their genetic make-up. Using state-of-the-art genomic technologies we analysed individuals with RCC who had clinical features (e.g. positive family history etc.) to suggest a possible underlying genetic cause. In addition to identifying known genetic cause of familial RCC, we also identified multiple genes that are known to predispose to cancer but had not been strongly linked to the development of kidney cancers. Further research is now ongoing to determine how this information is best utilised in the management of individuals with RCC in order that they and their relatives can benefit from earlier diagnosis. As our knowledge about how specific genetic cause of inherited RCC result in cancer predisposition advances, it becomes increasingly likely that there won’t be a single therapeutic approach to treating tumours that occur in individuals with genetic causes of RCC but rather that the approaches will differ between different genetic disorders. To facilitate the introduction of such “personalised cancer therapies” we have undertaken studies to identify the genetic basis of kidney cancer in individuals with features suggestive of an inherited form of RCC but no genetic variants in the genes which were currently known to cause familial RCC. Our studies using state-of-the-art genomic analysis techniques including whole genome sequencing implicate multiple genetic factors and suggest that each factor will only be relevant to a minority of patients. This makes the translation of these findings into clinical practice more challenging as there will only be a small data set for each candidate genetic factor but the indications are that when our findings are replicated and become part of clinical genetic testing, the characterisation of the genetic factor implicated in a specific family will determine the specific approach to treatment and family screening. To understand which therapeutic approach may be most suitable for individual inherited RCC subgroups we have been undertaking functional studies to elucidate mechanisms of tumourigenesis and how they might be targeted in different molecular subgroups. In addition, the treatment of metastatic cancers with targeted therapies will be enhanced by more sensitive methods to measure therapeutic responses and we have utilised metabolomics techniques to measure intra-tumour levels of oncogenic metabolites such as fumarate and succinate to identify fumarate hydratase and succinate dehydrogenase deficient cancers and proposed that such techniques will facilitate clinical trials for novel therapies in these disorders.