Coordinate Regulation of Oncogenic Signaling Pathways in SPOP Mutant Prostate Cancer

项目摘要/摘要 前列腺癌(PCa)是一种临床异质性疾病，患者个体差异显著。 结果。显著的分子异质性可能是不同的临床病程的基础，具有不同的分子。 最近确定的亚型。然而，新亚型的生物学含义和翻译影响是 很大程度上没有定义，迫切需要新的模型来研究生物学和治疗 这些新的PCA亚型的脆弱性。SPOP的反复突变发生在大约10%的PCa中， 定义一个独特的核心分子类的PCA。然而，SPOP突变驱动的机制 体内的前列腺癌发生机制尚不清楚。 利用SPOP突变体PCA的多种新的体外和体内模型，初步数据表明 这种SPOP突变导致了小鼠前列腺的肿瘤和浸润性癌症。此外，初步的 体内外模型研究支持SPOP突变激活肌醇磷脂3-激酶 (PI3K)信号通路，以及在人类前列腺癌中这一调控的证据。有趣的是，当PI3K激活时 正常情况下，雄激素受体(AR)信号会下调，我们发现SPOP突变会中断这一过程 通过上调AR实现负反馈。这些结果表明，SPOP突变激活了两个已知的关键基因 Pca-AR和PI3K信号中的信号通路。基于这些初步发现，我们假设 SPOP突变通过对AR和PI3K的协同调控推动前列腺癌的发生 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类 PCA样本建立SPOP调节PI3K/mTOR信号的机制基础，定义 PI3K/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，并确定在SPOP突变体中针对AR和PI3K/mTOR信号转导治疗的可能性 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的亚型。总之，这些研究将确定PI3K信号和AR信号在 由SPOP突变驱动的PCA，定义了SPOP突变体PCA中的关键信号事件以及更广泛的 在所有PCA亚型中的适用性，并为针对这一亚类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.