Dissecting and targeting a novel vulnerability in aggressive Rb1 and p53 doubly deficient prostate cancer

切割和靶向Rb1和P53双缺陷前列腺癌的一个新的易损性 前列腺癌是全世界男性第二常见的癌症，也是第二大致癌原因。 美国男人的死亡。Rb1和P53是两种典型的肿瘤抑制基因。丢失一个或两个等位基因 任何一种基因都会导致其功能的显著缺陷，从而导致肿瘤的发生和发展。 人类癌症，包括前列腺癌(PCa)。并发Rb1和P53缺乏症(RPD)在 侵袭性强、预后差的PCa病例。RPD癌症死亡率增加的机制-- 人们对前列腺癌的认识还远远不够，这阻碍了有效治疗方法的发展。我们的目标是 研究RPD PCA进展的机制，并针对RPD的新漏洞- PCa细胞。我们发现GPCRK3在RPD-PCa中的表达明显高于在RPD-PCa中的表达。 非RPD-PCA。与此相一致的是，GRK3的表达与Rb1缺失或P53缺失基因签名相关。vbl.使用 我们已经获得了调节GRK3的遗传和药理学工具，我们已经开始获得关键的 GRK3和RPD在前列腺癌中的作用机制。我们已经确定了一个关键的表观遗传调控因子，即 被GRK3激活，作为其激酶底物。我们的初步数据显示，GRK3沉默优先消融 RPD-Pca细胞，其基因敲除可抑制Pca进展并延长TRAMP小鼠的生存时间，RPD-Pca是一种 相关的基因工程小鼠(GEM)模型。我们基于这些结果的主要假设是 GRK3对RPD-PCa细胞的分子机制和适合性是必不可少的，并且GRK3 通过其底物传递信号是RPD侵袭性机制的重要组成部分。瞄准GRK3 为了剖析其在RPD细胞中作用的分子机制，我们建立了化合物文库 筛选并鉴定了两种有效的、一流的GRK3抑制剂，它们有效地阻断了GRK3的活性和 优先消融RPD-PCa细胞。我们还假设，用这些抑制剂阻断GRK3将 抑制RPD肿瘤生长和转移。为了验证这些假设，我们提出了三个目标：1. 通过在异种移植模型中检测GRK3沉默的影响，验证GRK3是RPD-PCA中的一个新的漏洞 及其基因敲除；2.确定GRK3抑制剂对GRK3的影响 RPD-Pca细胞的特性以及RPD-Pca细胞来源和患者来源的癌症进展 异种移植模型；3.剖析GRK3介导的RPD侵袭的分子机制。 这些工作的完成有望在RPD生物学基础上建立一种新的激酶-底物关系 并将GRK3定义为RPD-PCA的致命弱点。它还将验证以GRK3为目标作为 开发治疗致死性前列腺癌的有效疗法。我们的发现将对我们的理解和 瞄准RPD常见的其他侵袭性癌症类型。

Dissecting and targeting a novel vulnerability in Rb1 and p53 doubly deficient prostate cancer Prostate cancer is the second most common cancer in men worldwide and the second leading cause of cancer death in American men. Rb1 and p53 are two prototypical tumor suppressors. Loss of one or both alleles of either gene leads to significant deficiency in its functions, which contributes to the oncogenesis and progression of human cancers, including prostate cancer (PCa). Concurrent Rb1 and P53 Deficiency (RPD) is common in PCa cases that are aggressive and have poor prognosis. The mechanisms of increased cancer mortality in RPD- PCa are far from well understood, which has hindered the development of effective treatments. Our goal is to investigate the mechanisms underlying RPD PCa progression and to target novel vulnerabilities of RPD- PCa cells. We have found that GPCR-kinase 3 (GRK3) is expressed significantly higher in RPD-PCa than in non-RPD-PCa. In line with this, GRK3 expression correlates with Rb1-loss or p53-loss gene signatures. Using the genetic and pharmacological tools that we have acquired to modulate GRK3, we have begun to gain critical insights into the mechanisms of GRK3 and RPD in PCa. We have identified a key epigenetic regulator that is activated by GRK3 as its kinase substrate. Our preliminary data show that GRK3 silencing preferentially ablates RPD-PCa cells, and that its knockout inhibits PCa progression and extend survival of the TRAMP mice, a RPD- related genetically engineered mouse (GEM) model. Our overarching hypothesis based on these results is that GRK3 is essential for the molecular mechanisms and the fitness of RPD-PCa cells, and that GRK3 signaling through its substrates is a vital part of the mechanisms of RPD aggressiveness. To target GRK3 and to dissect molecular mechanisms underlying its function in RPD cells, we have carried out compound library screens and identified two potent and first-in-class GRK3 inhibitors which effectively block GRK3 activity and preferentially ablate RPD-PCa cells. We also hypothesize that blocking GRK3 with these inhibitors will thwart RPD tumor growth and metastasis. To test these hypotheses, we propose to pursue three Aims: 1. validate GRK3 as a novel vulnerability in RPD-PCa by examining the effects of its silencing in xenograft models and its knockout in a genetically defined RPD GEM model; 2. determine the impact of GRK3 inhibitors on the properties of RPD-PCa cells, as well as on the cancer progression in RPD-PCa cell-derived and patient-derived xenograft models; 3. dissect the molecular mechanisms underlying GRK3-mediated aggressiveness in RPD. Completion of these works is expected to establish a novel kinase-substrate relationship underlying RPD biology and define GRK3 as an Achilles heel of RPD-PCa. It will also validate targeting GRK3 as a new direction for developing effective therapeutics for lethal PCa. Our findings will have an impact on our understandings and targeting of other aggressive cancer types where RPD is common.