Genotypic Interactions in Brain Cancer Heterogeneity

描述（由申请人提供）：尽管对致病性病变有深入的了解，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个月生存期的改善微乎其微。一个中心问题，混淆成功的治疗是异质性，这种侵略性肿瘤。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，在GBM内存在多个和空间上不同的异型群体，使得任何病变或途径特异性治疗效果较差。虽然已经付出了很大的努力来理解异型肿瘤细胞和周围正常细胞之间的相互作用，但对这些肿瘤中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（存在于50%的病例中的标志性突变）通常以异质方式检测到，并且经常与结构改变相关。这些变化中最常见的是？EGFR（也称为de 2 - 7 EGFR、deltaEGFR和EGFR*）导致具有肿瘤增强能力的组成型活性突变受体。这种能力是缺乏从 扩增的wtEGFR，尽管其高度普遍的肿瘤表达相比，局灶性发生？EGFR对通过模拟这种类型的遗传异质性在体内，我们已经确定，IL-6旁分泌机制驱动？EGFR可以招募表达wtEGFR的细胞加速增殖，从而维持异质性。鉴于EGFR导向疗法的无效性，我们假设？EGFR/wtEGFR亚群相互作用不仅增强侵袭性肿瘤生长，而且在治疗抗性中起作用。 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抗性的机制。本研究将进行以下几方面的实验：1）遗传和生化分析 因为小鼠中的肿瘤异质性模型将决定关键的内在效应？2）质谱、遗传和生物化学分析将确定IL-6受体介导的wtEGFR的串扰激活的机制;和3）鉴定的效应物的遗传和药理学抑制将用于解偶联异型胶质瘤细胞相互作用以增强治疗功效。

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.