CHD1 and TAK1 Synthetic Lethality in Prostate Cancer

 描述（由申请人提供）：前列腺癌是一种以复发性基因缺失和扩增为特征的复杂疾病。人类遗传数据表明CHD 1和MAP 3 K7的双重缺失与致命的前列腺癌之间的相关性。我们最近在已发表和未发表的数据中表明，MAP 3 K7和CHD 1缺失导致侵袭性去势抵抗性前列腺癌。我们使用两个独立的模型系统进行了研究，为研究的总体结论提供了强有力的支持，这些研究提供了这两种新型肿瘤抑制剂与前列腺癌侵袭性之间的功能联系。因为MAP 3 K7和CHD 1都是肿瘤抑制因子，并且根据定义在前列腺癌中丢失或失活，所以两者都不是治疗策略的直接靶向。我们假设， MAP 3 K7和CHD 1依赖于新的生存途径，我们建议利用这些途径杀死已经失去MAP 3 K7和/或CHD 1的肿瘤。我们将使用两种互补的方法来识别治疗漏洞。在目标1中，我们将筛选敲低CHD 1和/或MAP 3 K7的人前列腺细胞，以获得常见前列腺癌药物在体外和体内抑制生长和肿瘤发生的能力。在目标2中，我们将使用全基因组shRNA筛选来鉴定缺失MAP 3 K7和/或CHD 1的细胞中的合成致死靶标。这是一个高风险、高收益的项目，适合R21类型的供资机制。每个目标都是独立的，每个目标都需要完成。这两个目标将共同定义一种极端侵袭性前列腺癌变体的潜在治疗方法。

 DESCRIPTION (provided by applicant): Prostate cancer is a complex disease characterized by recurrent gene deletions and amplifications. Human genetic data demonstrate correlation between dual loss of CHD1 and MAP3K7 with lethal prostate cancer. We recently showed in both published and unpublished data that MAP3K7 and CHD1 loss leads to aggressive castrate-resistant prostate cancer. We did this with two independent model systems providing strong support for the overall conclusions of the studies that provide a functional link between these two novel tumor suppressors and prostate cancer aggressiveness. Because MAP3K7 and CHD1 are both tumor suppressors, and by definition lost or inactivated in prostate cancer, neither are directly targetable with therapeutic strategies. We hypothesize that cells with loss of MAP3K7 and CHD1 have dependence on novel survival pathways and we propose to exploit these pathways to kill tumors that have lost MAP3K7 and/or CHD1. We will use two complementary approaches to identify therapeutic vulnerabilities. In Aim 1 we will screen human prostate cells with knockdown of CHD1 and/or MAP3K7 for the ability of common prostate cancer drugs to inhibit growth and tumorigenesis in vitro and in vivo. In aim 2 we will use a genome-wide shRNA screen to identify synthetic lethal targets in cells with loss of MAP3K7 and/or CHD1. This is a high-risk, high-gain project appropriate for an R21 type funding mechanism. Each aim is independent and each needs to be done. Together the two aims will define potential therapeutic approaches to an extremely aggressive variant of prostate cancer.