Control of histone demethylase activity: An innovative therapeutic concept to fight hormone refractory prostate cancer

• Applicant: Professor Dr. Roland Schüle
• Subject Area: Hematology, Oncology
• Term: from 2009 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 102806892

The events that lead to hormone refractory prostate cancer are still enigmatic and no curative treatment is available at present. Therefore novel therapeutic concepts are ultimately needed. Modulating the activities of histone demethylases and/or demethylase controlling signalling proteins is an innovative therapeutic concept to block tumour growth. This strategy is not targeting the androgen receptor directly but rather blocks androgen receptor function by inhibiting the activity of the associated histone demethylases. Thus, this novel therapeutic concept potentially preserves the tumour to develop hormone resistance. To achieve this concept, we plan to 1.) solve the crystal structures of the kinase PRK1 and the novel histone demethylase AOF1. Utilizing the crystal structures, we shall enter virtual screening campaigns combined with structure-based hit-to-lead optimisation to develop PRK1 and AOF1 inhibitors. 2.) We characterise the biological function of AOF1, and PRK1 in genetically modified mice and in tumour prone mouse models. 3.) We shall identify AOF1 and PRK1 target genes and AOF1-containing complexes by combing proteomic and bioinformatic approaches. We shall 4.) characterise signalling mechanisms that modify AOF1 and analyze the consequences of these modifications on biological function, especially tumour metastasis. 5.) We shall evaluate whether AOF1 is a predictive biomarker of metastasis.

• DFG Programme: Reinhart Koselleck Projects