CHD1 and TAK1 Synthetic Lethality in Prostate Cancer

 描述(申请人提供)：前列腺癌是一种以反复发生的基因缺失和扩增为特征的复杂疾病。人类遗传学数据显示CHD1和MAP3K7双重缺失与致命性前列腺癌相关。我们最近在已发表和未发表的数据中都表明，MAP3K7和CHD1缺失会导致侵袭性的去势抵抗前列腺癌。我们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，这些结论提供了这两个新的肿瘤抑制因子与前列腺癌侵袭性之间的功能联系。因为MAP3K7和CHD1都是肿瘤抑制因子，而且根据定义，在前列腺癌中丢失或失活，两者都不是治疗策略的直接靶点。我们假设丢失的细胞 MAP3K7和CHD1依赖于新的生存途径，我们建议利用这些途径来杀死失去MAP3K7和/或CHD1的肿瘤。我们将使用两种互补的方法来确定治疗的脆弱性。在目标1中，我们将筛选CHD1和/或MAP3K7基因敲除的人前列腺细胞，以了解常见前列腺癌药物在体外和体内抑制生长和肿瘤形成的能力。在目标2中，我们将使用全基因组shRNA筛选来识别丢失MAP3K7和/或CHD1的细胞中的合成致命靶点。这是一个适合R21型筹资机制的高风险、高收益项目。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具侵袭性的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 We recently showed in both published and unpublished data that MAP3K7 and CHD1 loss leads to aggressive castrate-resistant prostate cancer.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.