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

导致激素难治性前列腺癌的事件仍然是谜，目前没有治愈性治疗。因此，最终需要新的治疗概念。调节组蛋白脱甲基酶和/或脱甲基酶控制信号蛋白的活性是阻断肿瘤生长的创新治疗概念。这种策略不是直接靶向雄激素受体，而是通过抑制相关组蛋白脱甲基酶的活性来阻断雄激素受体功能。因此，这种新的治疗概念可能会使肿瘤产生激素抵抗。为了实现这一目标，我们计划：（1）解析了激酶PRK 1和新型组蛋白去甲基化酶AOF 1的晶体结构。利用晶体结构，我们将进入虚拟筛选活动，结合基于结构的命中铅优化开发PRK 1和AOF 1抑制剂。2.）的情况。我们在转基因小鼠和肿瘤易感小鼠模型中验证了AOF 1和PRK 1的生物学功能。3.）第三章我们将通过结合蛋白质组学和生物信息学方法鉴定AOF 1和PRK 1靶基因以及含有AOF 1的复合物。我们将（4）研究修饰AOF 1的信号传导机制，并分析这些修饰对生物学功能，特别是肿瘤转移的影响。5.）我们将评估AOF 1是否是转移的预测生物标志物。

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.