Coordinate Regulation of Oncogenic Signaling Pathways in SPOP Mutant Prostate Cancer

SPOP 突变前列腺癌中致癌信号通路的协调调控

• 批准号: 10772402
• 负责人: Christopher E Barbieri
• 金额: $ 36.1万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10772402
• 关键词: Address; Affect; Androgen Receptor; Androgens; Area; Automobile Driving; Biological; Biological Models; Biology; Cell Culture Techniques; Clinical; Clinical Course of Disease; Clinical Trials; DNA Sequence Alteration; Data; Development; Diagnosis; Disease; Event; FRAP1 gene; Feedback; Foundations; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genomics; Heterogeneity; Hormonal; Human; In Vitro; Insulin-Like Growth Factor I; Interruption; Intervention; Malignant Neoplasms; Malignant neoplasm of prostate; Modeling; Molecular; Mus; Mutation; NCOA3 gene; Nature; Neoplasms; Newly Diagnosed; Oncogenic; Organoids; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Phosphatidylinositols; Phosphotransferases; Prostate; Proteome; Publications; Receptor Signaling; Recurrence; Regulation; Reporting; Role; Sampling; Signal Pathway; Signal Transduction; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Up-Regulation; cancer invasiveness; cancer subtypes; clinical investigation; clinically relevant; cohort; human disease; human model; in vitro Model; in vivo; in vivo Model; insight; mTOR Inhibitor; men; molecular subtypes; mouse model; mutant; novel; novel diagnostics; novel therapeutic intervention; pharmacologic; prostate carcinogenesis; receptor; targeted treatment; therapeutic target; translational impact; ubiquitin-protein ligase

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.

项目摘要 /摘要 前列腺癌（PCA）是一种临床上异质性疾病，患者明显变化 结果。惊人的分子异质性可能是可变临床过程的基础，具有不同的分子 最近确定的子类型。但是，新型亚型的生物学意义和翻译影响是 在很大程度上不确定，新模型需要研究生物学和治疗 这些新型PCA亚型的脆弱性。 SPOP中的复发突变发生在大约10％的PCA中，并且 定义一个独特的核心分子类PCA。但是，旋转突变驱动的机制 体内前列腺肿瘤发生仍然未知。 使用多个新颖的体外和体内旋转突变体PCA模型，初步数据证明了 这种溅突变会驱动小鼠前列腺中的肿瘤和侵入性癌。此外，初步 在体外和体内支持的模型研究中，SPOP突变激活了磷酸肌醇3-激酶 （PI3K）信号通路，并在人PCA中进行此调节的证据。有趣的是，PI3K激活 通常下调雄激素受体（AR）信号传导，我们表明SPOP突变中断了这一点 通过上调AR来反馈。这些结果表明，SPOP突变激活了两个已知的临界 PCA - AR和PI3K信号传导中的信号通路。基于这些初步发现，我们假设 这种溅突变通过AR和PI3K的坐标调节驱动前列腺肿瘤发生 信号通路。为了解决这一假设，我们将利用新颖的体外和体内模型和人类 PCA样品建立PI3K/mTOR信号调节的机械基础，定义 PI3K/MTOR和AR信号在驱动形成和SPOP突变体的进展中的相对重要性 PCA，并确定SPOP突变体中AR和PI3K/MTOR信号的治疗靶向的潜力 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钥匙 PCA的亚型。这些研究将共同​​确定PI3K信号传导和AR信号传导的重要性 由SPOP突变驱动的PCA，定义SPOP突变体PCA中的关键信号事件，更宽 PCA亚型的适用性，并为针对此子类的临床试验奠定了基础。