Genotypic Interactions in Brain Cancer Heterogeneity

脑癌异质性中的基因型相互作用

基本信息

批准号：
8677987
负责人：
Frank Furnari
金额：
$ 35.28万
依托单位：
LUDWIG INSTITUTE FOR CANCER RES LTD
依托单位国家：
美国
项目类别：
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/8677987
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 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 fluorescence molecular tomography 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 tool tumor tumor growth

项目摘要

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.

描述（由申请人提供）：尽管有深入了解致病性病变和神经外科手术，放射治疗和临床试验的数十年的进步，但胶质母细胞瘤（GBM）患者的12-15个月生存率的最小改善仍达到了最小的改善。混淆成功治疗的一个核心问题是这种侵略性肿瘤的异质性质。这种异质性在表型上作为混合细胞学亚型，基因型作为突变和基因扩增，在基因表达中作为区域差异在转录上以转录为单位。结果，多种和空间上不同的异型种群存在于GBM内，使任何病变或途径特异性疗法的有效性降低。尽管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已有很多努力，但对这些肿瘤中异质性肿瘤细胞之间的相互作用的了解少得多。在GBM中，通常以异质方式检测到表皮生长因子受体的扩增，这是50％的病例中存在的标志性突变，并且经常与结构改变有关。这些变化中最常见的？这种能力缺乏尽管与局部发生的？通过在体内建模这种类型的遗传异质性，我们确定了由？鉴于EGFR指导的治疗剂的无效性，我们假设？该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性抗性的机制。将进行以下实验线：1）遗传和生化分析随着小鼠的肿瘤异质性建模将确定介导异质性维持的固有的关键效应子和WTEGFR信号传导； 2）质谱，遗传和生化分析将确定WTEGFR的IL-6受体介导的交叉激活的机制； 3）遗传和药理抑制已鉴定的效应子将用于取消异型胶质瘤细胞相互作用，以增强治疗功效。