The study of underlying mechanism of EGFR-Ras signaling in glioblastoma

胶质母细胞瘤中EGFR-Ras信号传导机制的研究

• 批准号: 8552936
• 负责人: Terry van Dyke
• 金额: $ 65.22万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552936
• 关键词: Adult; Anaplastic astrocytoma; Astrocytes; Astrocytoma; Clinic; Clinical; Clinical Data; Development; Disease; Engineering; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Etiology; Event; Family member; Fluorescent in Situ Hybridization; Future; Gene Expression Profile; Genes; Genetically Engineered Mouse; Glioblastoma; Goals; Heterogeneity; Human; Immunohistochemistry; In Vitro; Malignant - descriptor; Malignant Neoplasms; Mesenchymal; Missense Mutation; Modeling; Molecular; Morphology; Mus; Mutate; Mutation; PTEN gene; Pathway Analysis; Pathway interactions; Patients; Play; Primary Brain Neoplasms; Process; Property; Proteins; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Relative (related person); Research; Resistance; Retinoblastoma Protein; Role; Signal Transduction; System; Tumor Cell Line; Tumor Suppression; Work; Yang; Yin; effective therapy; in vivo; inhibitor/antagonist; insight; mortality; mouse model; new therapeutic target; outcome forecast; overexpression; tumor; tumor progression; tumorigenesis

High grade astrocytomas (HGA) remain fatal without effective treatment. Using an inducible Cre-driven adult astrocyte-specific system, we explored the relative roles of key pathways perturbed in human glioblastomas (grade IV; GBM) in initiation and progression of HGA. The likely event combinations (engineered and spontaneous) yielding disease indicate grade-specific roles for each aberration and suggest specific progression mechanisms from grade II [induced only by pRb-tumor suppression (TS) inactivation] to III (addition of KrasG12D activation, with spontaneous inactivation of p53 by mutation or mislocalization), to Grade IV [further addition of PTEN inactivation (spontaneous or engineered)] without IDH1 mutation. In the transition from grade II to III disease and subsequent to KrasG12D activation, Trp53 missense mutations congruent with human GBM mutations. This study underscores the importance of stochastic events with evident tumor heterogeneity in order to recapitulate disease properties. Importantly, murine GBM transcriptomes showed concordance with the highly aggressive human mesenchymal GBM subclass.To determine whether EGFR played a role on tumor progression in our astrocytoma mouse model with inactivation of Rb-TS and activation of KrasG12D (TR model), we performed immunohistochemistry (IHC) study and FISH analysis on TR tumors, and found that EGFR was amplified/overexpressed. Inhibition of EGFR by EGFR inhibitor Erlotinib showed resistance in vivo and in vitro on TR tumors, which is consistent with the human clinical data. However, these tumors showed sensitivity to multiple RTK inhibitors in vitro, indicating that other RTKs may compensate for single EGFR inhibition. We are currently working on molecular pathway analysis to dissect the compensatory mechanism of EGFR inhibition. Song Y, Zhang Q, Bash R, Kutlu B, Difilippantonio S, Yin C, Gilbert D, Wang C, Yang C, Bullitt E, Kafri T, McCarthy K, Louis D, Hood L, Miller CR, Van Dyke T. An evolutionary path to glioblastoma: Insight into etiology from engineered mice. (Under review at Cancer Discovery)

如果没有有效的治疗，高级别星形细胞瘤(HGA)仍然是致命的。使用可诱导的Cre驱动的成人星形胶质细胞特异性系统，我们探索了人胶质母细胞瘤中受干扰的关键通路(IV级；GBM)在HGA的发生和发展中的相对作用。可能的事件组合(工程性和自发性)导致的疾病表明了每个异常的级别特定的作用，并提出了特定的进展机制，从II级[仅由pRB肿瘤抑制(TS)失活引起]到III级(增加KrasG12D激活，由于突变或错误定位而自发失活P53)，到IV级[进一步增加PTEN失活(自发或工程性的)]，而没有IDH1突变。在从II级到III级疾病的转变过程中，KrasG12D激活后，TrP53错义突变与人GBM突变一致。这项研究强调了具有明显肿瘤异质性的随机事件的重要性，以重述疾病特性。重要的是，小鼠的GBM转录本显示出与高度侵袭性的人间充质GBM亚类一致。为了确定EGFR在RB-TS失活和KrasG12D激活的星形细胞瘤小鼠模型(TR模型)中是否在肿瘤进展中发挥作用，我们对TR肿瘤进行了免疫组织化学(IHC)研究和FISH分析，发现EGFR被扩增/过表达。EGFR抑制剂Erlotinib抑制EGFR对肿瘤的体内外耐药，这与人类的临床资料一致。然而，这些肿瘤在体外对多种RTK抑制剂表现出敏感性，表明其他RTK可能补偿单一的EGFR抑制。我们目前正在进行分子通路分析，以剖析EGFR抑制的代偿机制。宋勇，张Q，Bash R，Kutlu B，Difilippantonio S，Yen C，Gilbert D，Wang C，Yang C，Bullitt E，Kafri T，McCarthy K，Louis D，Hood L，Miller CR，Van Dyke T。胶质母细胞瘤的进化路径：来自工程小鼠的病因学洞察。(《癌症发现》杂志正在审查中)