Genetic network analysis of cancer targets

描述（由申请人提供）：髓母细胞瘤是儿童常见的致残性肿瘤，目前的治疗方法往往无效。转录因子MYC和MYCN在大多数这些肿瘤中表达，但基本上是不可靶向的。该申请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和现有治疗方法的新作用。我们的工作部分集中在组织特异性网络，区分MYC和MYCN在正常小鼠小脑，并在小鼠模型的MYC和MYCN驱动的髓母细胞瘤。我们将通过分析皮肤和皮肤癌中的小鼠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。我们目前的初步数据，利用这种方法来确定GABA受体作为新的目标，髓母细胞瘤。这项研究建立了一种在正常小鼠体细胞和癌症组织中开发小鼠遗传网络的一般方法，并将其作为人类癌症的过滤器，以识别新的靶点。我们的目标是：A1。开发一种综合的生物信息学筛选和小鼠模型方法，以确定癌症靶点。我们表征了来自大型基因分型小鼠回交的正常皮肤、脑和肺中的共表达网络，其中22个组织被保存用于trans-CTDD项目。A2.基于我们的综合小鼠-人类生物信息学方法产生的数据，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在这种常见和致命的儿童癌症中进行治疗。A3.确定髓母细胞瘤中与MYC和/或MYCN相关的靶点。成功完成鉴定了髓母细胞瘤中MYC和MYCN相关的特征和靶点，可能适用于MYC和MYCN驱动的癌症谱。

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.