An integrative approach to target lineage-specific oncogenic transcription factor

描述(由申请人提供) 摘要：许多谱系特异性转录因子在不同癌症类型的发病机制中具有明确的致癌作用。然而，除了配体结合的核转录因子(即AR、ER、RAR)外，大多数都被认为是“不可用药”的，因为它们缺乏常规的“可用药”口袋和用于合理药物设计的模型化合物。更重要的是，转录因子通过鲜为人知的复杂机制调节大量的转录靶标，通常是以细胞/组织谱系依赖的方式，这使得设计适合高通量筛选的敏感和特异的读数变得困难。我们建议使用一种创新的方法，将基于高通量RNAi的筛查与基于高复杂性基因签名的读数相结合，系统地发现在不同的ETS依赖的癌症类型中，即GIST和前列腺癌和黑色素瘤的亚型中，可以特异性干扰致癌ETS家族转录程序的“可用药”靶点。ETS依赖的基因签名是通过对ETS依赖的转录本、ETS全基因组定位研究和每种不同的ETS依赖的癌症类型的表观遗传学特征的综合分析得出的。这种方法如果被证明是成功的，无疑将产生针对致癌ETS转录因子和ETS依赖基因签名的新的治疗靶点，作为生物标记物，可以直接转化为人类临床研究。此外，这种综合方法可以推广到针对其他家族特定的致癌转录因子在其相关的恶性肿瘤。 公共卫生相关性：癌基因转录因子在推动肿瘤发生方面具有公认的作用，特别是在特定组织/细胞谱系的相关癌症类型中，它们是这些恶性肿瘤的理想治疗靶点。然而，针对癌基因转录因子的治疗发展一直受到它们的结构特性的阻碍，并且缺乏能够高通量筛选的敏感和特异的高复杂性转录读数。这项建议描述了一种新的综合方法，它结合了基于高通量RNAi的筛选和基于高复杂性基因签名的读出，以系统地发现癌基因转录因子的可用药修饰因子。

DESCRIPTION (Provided by the applicant) Abstract: Many lineage-specific transcription factors have well-defined oncogenic roles in the pathogenesis of distinct cancer types. However, with the exception of ligand binding nuclear transcription factors (i.e. AR, ER, RAR¿), the majority of them are considered ""undruggable"" because they lack the conventional ""druggable"" pockets and model compounds for rational drug design. More importantly, transcription factors regulate large repertoire of transcriptional targets through poorly understood complex mechanisms often in a cell/tissue lineage-dependent manner, making it difficult to design sensitive and specific readouts amenable for high throughput screening. We propose to use an innovative approach that combines a high- throughput RNAi-based screening with high-complexity gene-signature based readouts to systematically discover ""druggable"" targets that can specifically interfere with oncogenic ETS- family transcriptional program in distinct ETS-dependent cancer types, i.e., GIST and subsets of prostate cancer and melanoma. The ETS-dependent gene-signature is derived from integrative analyses of ETS-dependent transcriptomes, ETS genome-wide localization studies and the epigenetic landscapes in each distinct ETS-dependent cancer type. This approach, if proven successful, will undoubtedly generate novel therapeutic targets specific for oncogenic ETS- transcription factors and ETS-dependent-gene-signatures as biomarkers that can be directly translated into human clinical studies. Moreover, this integrative approach can be generalized to target other families of lineage-specific oncogenic transcription factors in their relevant malignancies. Public Health Relevance: Oncogenic transcription factors have well-established roles in driving oncogenesis especially in the relevant cancer types of specific tissue/cell lineages, and they represent the ideal therapeutic targets in the these malignancies. However, therapeutic development to specifically target oncogenic transcription factors has been hindered by their structural properties and lack of sensitive and specific high-complexity transcriptional readout amenable for high throughput screening. This proposal describes a novel integrative approach that combines a high throughput RNAi-based screen with high complexity gene-signature based readout to systematically discover druggable modifiers of oncogenic transcription factors.