Genotypic Interactions in Brain Cancer Heterogeneity

脑癌异质性中的基因型相互作用

• 批准号: 8538528
• 负责人: Frank Furnari
• 金额: $ 34.39万
• 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/8538528
• 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.

描述（由申请人提供）：尽管对致病性病变有了深入的了解，并且在神经外科、放射治疗和临床试验方面取得了数十年的进展，但多形性胶质母细胞瘤（GBM）患者的 12-15 个月生存率仍取得了最小的改善。阻碍成功治疗的一个核心问题是这种侵袭性肿瘤的异质性。这种异质性在表型上表现为混合细胞学亚型，在基因型上表现为突变和基因扩增，在转录上表现为基因表达的区域差异。因此，GBM 内存在多个空间上不同的异型群体，使得任何病变或途径特异性治疗的效果较差。尽管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付出了很多努力，但对这些肿瘤内异质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 50% 病例中存在的标志性突变，通常以异质方式检测到，并且经常与结构改变相关。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组成型活性突变受体。这种能力是缺乏的 尽管与局灶性发生的 EGFR 相比，wtEGFR 具有高度普遍的肿瘤表达，但 wtEGFR 仍被扩增。通过体内模拟这种类型的遗传异质性，我们确定由 EGFR 驱动的 IL-6 旁分泌机制可以招募 wtEGFR 表达细胞加速增殖，从而维持异质性。鉴于 EGFR 导向治疗的无效性，我们假设 EGFR/wtEGFR 亚群相互作用不仅增强侵袭性肿瘤生长，而且在治疗耐药性中发挥作用。 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耐药性的机制。将进行以下实验：1）遗传和生化分析 因为小鼠肿瘤异质性模型将确定介导异质性维持的 EGFR 和 wtEGFR 信号传导固有的关键效应子； 2) 质谱、遗传和生化分析将确定IL-6受体介导的wtEGFR串扰激活的机制； 3）对已识别效应子的遗传和药理学抑制将用于解开异型神经胶质瘤细胞的相互作用，以增强治疗效果。