P5: Dissection of KMT9 biology in urothelial carcinoma

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Epigenetic writers such as histone methyltransferases play key roles in the control of physiology and pathology. Our preparatory data establish the biological relevance of the histone methyltransferases KMT9 and identify KMT9 as a promising target for therapeutic intervention of bladder cancer. We solved the crystal structure of KMT9, implemented a structure-guided KMT9 inhibitor programme and developed drug-like small molecule KMT9 inhibitors (KMT9i). KMT9i display selectivity against all currently known SET-domain and 7-beta-strand histone methyltransferases, high potency in biochemical and cellular assays, and severely impair growth of bladder cancer cells. To promote the path of KMT9 inhibition to clinical phase I testing in bladder cancer, we propose to combine in vivo analyses using mouse genetics and small-molecule KMT9 inhibitors to interrogate specific aspects of the genetics of bladder cancer in vivo and in organoid culture systems. This detailed analysis will greatly enhance our understanding of KMT9 function in bladder cancer and provide a comprehensive view of KMT9 action. In particular, we will uncover the impact of KMT9 on oncogenic PTEN signalling and cell cycle regulation by TP53. Consequently, we aim (1) to evaluate the therapeutic potential of Kmt9-alpha loss (KMT9 KO) and inhibition (KMT9i) in the Pten/Trp53 deletion (Pten/Trp53 KO) bladder cancer model in vitro and in vivo. Furthermore, we propose (2) to dissect and the different mechanistic underpinnings of KMT9 action in normal bladder and urothelial carcinoma. Collaborations with the other UcarE groups will allow us to translate the findings made in our mouse studies to human bladder cancer samples, organoids and cell lines, as well as to carry out extensive pre-clinical testing of our KMT9 inhibitors. This proposal will broaden our knowledge and the perspectives on the utility of KMT9 inhibition for therapeutic intervention and provide advanced mechanistic understanding of KMT9 biology.