Genetic network analysis of cancer targets

描述(申请人提供)：髓母细胞瘤是一种常见的儿童致残性肿瘤，目前的治疗方法往往无效。转录因子MYC和MYCN在大多数肿瘤中都有表达，但基本上是非靶向性的。这项应用的长期目标是将人类肿瘤的基因组筛选与小鼠共表达网络相结合，以确定新的癌症靶点，以及现有治疗方法的途径的新角色。我们将这项工作的一部分集中在区分正常小鼠小脑中的MYC和MYCN以及MYC和MYCN驱动的髓母细胞瘤小鼠模型中的组织特异性网络上。我们将通过分析小鼠皮肤和皮肤癌中MYC和MYCN驱动的网络，并使用人类遗传学和基因组数据集来筛选潜在的靶点。我们利用这一方法提供了初步数据，以确定GABA受体是髓母细胞瘤的新靶点。这项研究建立了一种在正常小鼠体细胞和癌症组织中建立小鼠遗传网络的一般方法，并将其应用于人类癌症，以识别新的靶点。我们的具体目标是：1.开发一种综合生物信息学筛查和小鼠模型方法来识别癌症靶点。我们从一个大的基因分型的小鼠回交中鉴定了正常皮肤、脑和肺中的共表达网络，其中22个组织被保存用于反式CTDD项目。A2.基于我们整合的鼠-人生物信息学方法得出的数据，我们将验证GABA受体作为MB的治疗靶点，以及用于神经和精神疾病的生物活性药物是否可以用于这种常见的致命儿童癌症的治疗。A3.确定髓母细胞瘤中与MYC和/或MYCN相关的靶点。成功的完成确定了髓母细胞瘤中与MYC和MYCN相关的签名和靶点，可能适用于MYC和MYCN驱动的一系列癌症。

DESCRIPTION (provided by applicant): Medulloblastoma is a common and disabling tumor of children, for which current therapies are often ineffective. The transcription factors MYC and MYCN are expressed in the majority of these tumors, but are essentially untargetable. The long-term objective of this application is to integrate genomic screening of human tumors with mouse co-expression networks to identify both new cancer targets, and novel roles for pathways with existing therapeutics. We focus this effort in-part on tissue-specific networks that distinguish MYC and MYCN in in normal murine cerebellum, and in mouse models of MYC and MYCN-driven medulloblastoma. We will filter potential targets through analysis of murine MYC and MYCN driven networks in skin and in skin cancer, and using human genetics and genomic datasets. We present preliminary data utilizing this methodology to identify GABA receptors as novel targets in medulloblasotma. This study establishes a general method of developing murine genetic networks in normal murine somatic and cancer tissues, and applying these as a filter to human cancer, to identify new targets. Our specific aims are: A1. Develop an integrated bioinformatics screening and mouse models approach to identify cancer targets. We characterized co-expression networks in normal skin, brain, and lung from a large genotyped mouse back- cross, from which 22 tissues are preserved for trans-CTDD projects. A2. Based on data resulting from our integrated mouse-human bioinformatics approach, we will validate GABA receptors as therapeutic targets in MB, and whether bioactive drugs used in neurological and psychiatric disorders can be leveraged therapeutically in this common and lethal childhood cancer. A3. To identify targets associated with MYC and/or MYCN in medulloblastoma. Successful completion identifies MYC and MYCN-associated signature and targets in medulloblastoma, potentially applicable across a spectrum of MYC and MYCN-driven cancers.