Genotypic Interactions in Brain Cancer Heterogeneity

描述（由申请人提供）：尽管对致病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个月生存率仍有微小的改善。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。这种异质性在表型上表现为混合的细胞学亚型，在基因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中存在多个和空间上不同的异型群体，使得任何病变或通路特异性治疗效果较差。虽然人们已经努力了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（50%病例中存在的标志性突变）通常以异质方式检测到，并且通常与结构改变相关。这些改变中最常见的是？EGFR（也称为de2-7EGFR、deltaEGFR和EGFR*）是一种具有肿瘤增强能力的本构活性突变受体。这种能力是缺乏的

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.