Genotypic Interactions in Brain Cancer Heterogeneity

脑癌异质性中的基因型相互作用

• 批准号: 8420244
• 负责人: Frank Furnari
• 金额: $ 35.85万
• 依托单位: LUDWIG INSTITUTE FOR CANCER RES LTD
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8420244
• 关键词: Adult; Agar; Astrocytes; Attention; Biochemical; Cell Communication; Cell Proliferation; Cells; Cisplatin; Clinical; Complex; Conditioned Culture Media; Development; Docking; Drug resistance; Engraftment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Fluorescence; Gene Amplification; Gene Expression; Genes; Genetic; Genetic Heterogeneity; Glioblastoma; Glioma; Goals; Growth; Heterogeneity; Human; Image; Interleukin-6; Knowledge; Label; Lead; Lesion; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Mass Spectrum Analysis; Mediating; Minority; Mixed Neoplasm; Modeling; Molecular; Monitor; Mus; Mutation; Nature; Neoplasms; Normal Cell; Oncogenic; Outcome; PTEN gene; Pathway interactions; Patients; Phenotype; Phosphotyrosine; Play; Population; Primary Brain Neoplasms; Production; Proteins; Radiation therapy; Receptor Activation; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Resistance; Resolution; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Staining method; Stains; Stromal Cells; Testing; Therapeutic; Therapeutic Agents; Therapy Clinical Trials; Time; Tissues; Treatment Efficacy; Tumorigenicity; Variant; Vincristine; base; cancer cell; cell type; cytokine; epidermal growth factor receptor VIII; glioma cell line; improved; in vivo; insight; loss of function; mutant; neoplastic cell; neurosurgery; novel therapeutic intervention; paracrine; receptor; receptor expression; regional difference; research study; small hairpin RNA; temozolomide; therapeutic target; tomography; tool; tumor; tumor growth

DESCRIPTION (provided by applicant): Minimal improvement in the 12-15 month survival of patients with glioblastoma mutliforme (GBM) has been achieved despite in depth knowledge of pathogenic lesions and decades of advances in neurosurgery, radiation therapy and clinical trials. A central issue that confounds successful treatment is the heterogeneous nature of this aggressive tumor. This heterogeneity presents phenotypically as mixed cytological subtypes, genotypically as mutations and gene amplifications, and transcriptionally as regional differences in gene expression. As a result, multiple and spatially distinct heterotypic populations exist within a GBM, making any lesion- or pathway-specific therapy less effective. While much effort has been placed on understanding the interactions between heterotypic tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within these neoplasms. In GBM, amplification of the epidermal growth factor receptor, a hallmark mutation present in 50% of cases, is often detected in a heterogeneous manner and frequently associated with structural alterations. The most common of these alterations, ?EGFR, (also known as de2-7EGFR, deltaEGFR and EGFR*) results in a constitutively active mutant receptor with tumor enhancing capability. This ability is lacking from amplified wtEGFR despite its highly pervasive tumor expression in comparison to focally occurring ?EGFR. By modeling this type of genetic heterogeneity in vivo, we have determined that an IL-6 paracrine mechanism driven by ?EGFR can recruit wtEGFR-expressing cells into accelerated proliferation and therefore result in the maintenance of heterogeneity. Given the ineffectiveness of EGFR-directed therapeutics, we postulate that ?EGFR/wtEGFR sub-population interactions not only enhance aggressive tumor growth but also play a role in therapeutic resistance. The overall goal of this project is to dissect the mechanisms whereby GBM receptor heterogeneity drives tumor aggressiveness and therapeutic resistance. The following lines of experimentation will be carried out: 1) genetic and biochemical analysis as well as tumor heterogeneity modeling in mice will determine critical effectors intrinsic to ?EGFR- and wtEGFR- signaling that mediate heterogeneity maintenance; 2) mass spectrometry, genetic and biochemical analysis will determine the mechanism of IL-6 receptor-mediated cross- talk activation of wtEGFR; and 3) genetic and pharmacological inhibition of identified effectors will be used to uncouple heterotypic glioma cell interactions to enhance therapeutic efficacy. PUBLIC HEALTH RELEVANCE: Glioblastoma multiforme (GBM), the most common primary brain tumor in adults is a highly invasive, neurologically destructive tumor with a survival range of 12-15 months, despite maximum treatment efforts. A central issue that contributes to this lack of successful treatment is the tumor's heterogeneous or varied cell type composition. As a result, multiple and spatially distinct tumor cell populations exist within a typical GBM, making any single therapy less effective. This proposal will identify the genes and mechanisms that promote GBM heterogeneity. These insights will lead to new tools for improving the efficacy of known therapeutic agents as well as for the development of new therapeutic approaches.

描述(由申请人提供)：尽管对致病病变有深入的了解，并在神经外科、放射治疗和临床试验方面取得了数十年的进步，但变形性胶质母细胞瘤(GBM)患者的12-15个月存活率仍取得了极小的改善。困扰成功治疗的一个中心问题是这种侵袭性肿瘤的异质性。这种异质性表现为混合细胞学亚型，遗传型表现为突变和基因扩增，转录表现为基因表达的区域性差异。因此，基底膜内存在多个空间上不同的异型群体，使得任何针对病变或路径的治疗效果较差。虽然人们在了解异型肿瘤细胞与周围正常细胞之间的相互作用方面做了很多工作，但对这些肿瘤内异质性肿瘤细胞之间的相互作用知之甚少。在GBM中，表皮生长因子受体的扩增是一种标志性突变，存在于50%的病例中，通常以不同的方式检测到，并经常与结构变化相关。这些改变中最常见的是？EGFR(也称为de2-7EGFR、deltaEGFR和EGFR*)，导致具有肿瘤增强能力的结构性活性突变受体。这种能力是缺乏的 扩增的wtEGFR，尽管与灶性发生的EGFR相比，它在肿瘤中的表达非常普遍。通过在体内模拟这种类型的遗传异质性，我们确定了由EGFR驱动的IL-6旁分泌机制可以招募表达wtEGFR的细胞加速增殖，从而导致异质性的维持。鉴于EGFR导向治疗的无效性，我们推测？EGFR/wtEGFR亚群的相互作用不仅促进了侵袭性肿瘤的生长，而且在治疗抵抗中发挥了作用。这个项目的总体目标是剖析GBM受体异质性驱动肿瘤侵袭性和治疗耐药的机制。将进行以下几个方面的实验：1)遗传和生化分析 由于小鼠肿瘤异质性建模将确定介导异质性维持的EGFR和wtEGFR信号所固有的关键效应分子；2)质谱学、遗传学和生化分析将确定IL-6受体介导的wtEGFR串扰激活的机制；以及3)已识别的效应分子的遗传和药物抑制将被用于解偶联异型胶质瘤细胞相互作用，以提高治疗效果。 公共卫生相关性：多形性胶质母细胞瘤(GBM)是成人最常见的原发脑肿瘤，是一种高度侵袭性、神经破坏性的肿瘤，尽管进行了最大限度的治疗，但生存期为12-15个月。导致这种缺乏成功治疗的一个中心问题是肿瘤的异质性或不同的细胞类型组成。其结果是，在典型的基底膜内存在多个空间上不同的肿瘤细胞群，使得任何单一治疗效果都较差。这项建议将确定促进GBM异质性的基因和机制。这些见解将导致新的工具，以提高已知的治疗剂的疗效，以及开发新的治疗方法。