Coordinate Regulation of Oncogenic Signaling Pathways in SPOP Mutant Prostate Cancer

项目概要/摘要 前列腺癌（PCa）是一种临床异质性疾病，在患者中具有显著的变异性， 成果。显著的分子异质性可能是可变的临床过程的基础，具有不同的分子生物学特性。 最近发现的亚型。然而，新亚型的生物学意义和翻译影响是 在很大程度上是不确定的，迫切需要新的模型来研究生物学和治疗方法。 这些新型PCa亚型的脆弱性。SPOP的复发突变发生在约10%的PCa中， 定义了PCa的一个独特的核心分子类别。然而，SPOP突变驱动 体内前列腺肿瘤发生仍然未知。 使用SPOP突变型PCa的多种新的体外和体内模型，初步数据表明， SPOP突变导致小鼠前列腺的肿瘤和浸润性癌症。此外，初步 体外和体内模型研究支持SPOP突变激活磷酸肌醇3-激酶 （PI 3 K）信号通路，在人类PCa中有这种调节的证据。有趣的是，虽然PI 3 K激活 通常下调雄激素受体（AR）信号，我们发现SPOP突变中断了这一点， 通过上调AR产生负反馈。这些结果表明，SPOP突变激活了两个已知的关键 在PCa-AR和PI 3 K信号传导中的信号传导途径。基于这些初步发现，我们假设 SPOP突变通过协调调节AR和PI 3 K驱动前列腺肿瘤发生 信号通路为了解决这一假设，我们将利用新的体外和体内模型和人 PCa样本建立SPOP调节PI 3 K/mTOR信号传导的机制基础，定义 PI 3 K/mTOR和AR信号在驱动SPOP突变体形成和进展中的相对重要性 PCa，并确定SPOP突变体中AR和PI 3 K/mTOR信号传导的治疗靶向潜力 PCa。 该项目利用独特的体内和体外模型系统来研究最近发现的关键 PCa亚型。总之，这些研究将确立PI 3 K信号传导和AR信号传导在 由SPOP突变驱动的PCa，定义了SPOP突变型PCa中的关键信号事件， 本发明的目的是提供跨PCa亚型的适用性，并为针对该亚型的临床试验提供基础。

Project Summary / Abstract Prostate cancer (PCa) is a clinically heterogeneous disease, with marked variability in patient outcomes. Striking molecular heterogeneity may underlie the variable clinical course, with distinct molecular subtypes recently identified. However, the biologic implications and translational impact of novel subtypes are largely undefined, and there is a critical need for new models to study the biology and therapeutic vulnerabilities of these novel subtypes of PCa. Recurrent mutations in SPOP occur in about 10% of PCa, and define a distinct, core molecular class of PCa. However, the mechanisms by which SPOP mutation drives prostate tumorigenesis in vivo remain unknown. Using multiple novel in vitro and in vivo models of SPOP mutant PCa, preliminary data demonstrate that SPOP mutation drives neoplasia and invasive cancer in the mouse prostate. Furthermore, preliminary studies in models in vitro and in vivo support that SPOP mutation activates the phospho-inositide 3-kinase (PI3K) signaling pathway, with evidence for this regulation in human PCa. Interestingly, while PI3K activation normally downregulates androgen receptor (AR) signaling, we show that SPOP mutation interrupts this negative feedback by upregulating AR. These results suggest that SPOP mutation activates two known critical signaling pathways in PCa – AR and PI3K signaling. Based on these preliminary findings, we hypothesize that SPOP mutation drives prostate tumorigenesis through coordinate regulation of AR and PI3K signaling pathways. To address this hypothesis, we will utilize novel in vitro and in vivo models and human PCa samples to establish the mechanistic basis of SPOP regulation of PI3K/mTOR signaling, define the relative importance of PI3K/mTOR and AR signaling in driving formation and progression of SPOP mutant PCa, and determine the potential for therapeutic targeting of AR and PI3K/mTOR signaling in SPOP mutant PCa. This project leverages unique in vivo and in vitro model systems to study a recently discovered key subtype of PCa. Together, these studies will establish the importance of PI3K signaling and AR signaling in PCa driven by SPOP mutations, define the critical signaling events in SPOP mutant PCa and the broader applicability across PCa subtypes, and provide the foundation for clinical trials targeting this subclass.