Evolution of cancer-specific molecular requirements for glioblastoma multiforme (

描述（由申请人提供）：在癌症生物学中，很明显，对特定基因活性的要求在癌症类型中可能存在很大差异。这些差异可能是由组织或细胞类型固有的特定环境分子限制引起的。 癌症的起源和发展过程本身。我们目前缺乏对癌症特异性基因需求和驱动其需求的过程的了解，这阻碍了癌症靶向治疗策略的发展。然而，在过去五年中，在用于患者癌症的培养系统的开发方面已经取得了重大进展，该培养系统允许前所未有地接近癌症进化的分子途径和细胞表型。在过去的三年里，我们已经开发出一种策略，用于定义患者癌症样本中基因需求的性质。我们的方法将来自患者来源的癌症干细胞的功能遗传筛选的数据与从“癌症组学”数据集构建的网络模型相结合，以进行基因需求预测。在多形性胶质母细胞瘤（GBM）（一种无法治愈的脑癌形式）的概念验证研究中，我们已经证明了GBM致死基因的存在，当其被抑制时，患者GBM肿瘤细胞对细胞转化引起的细胞应激敏感。 在本申请中，我们使用这种癌症致死预测范例来解决挑衅性问题8：为什么某些突变事件在某些组织中促进癌症表型，而不是其他组织？我们检验了GBM对基因活性的特定要求来自三个特定环境约束之一的假设：（a）起源组织（即，（B）GBM特异性 进化过程;或（c）一般的细胞转化过程。我们的实验方法将结合联合收割机数据从功能基因筛选人类GBM干细胞（多种亚型）与预先存在的贝叶斯网络模型GBM和其他癌症，包括乳腺癌，肺癌，卵巢癌，前列腺癌（从癌症基因组图谱患者数据集生成）。 如果成功，这些研究将揭示GBM特定要求的范围和起源 GBM患者样本中的基因活性除了提供对脑肿瘤生物学的关键见解外，这些研究还将显著有助于确定GBM和其他癌症的新靶向治疗策略，这些癌症的标准治疗方法具有较差的治疗窗口。

DESCRIPTION (provided by applicant): In cancer biology it has become evident that requirements for specific gene activities can vary widely across cancer types. These differences presumably arise from context-specific molecular constrains intrinsic to the tissue or cell type of origin and to the process of cancer development itself. Our current lack of knowledge of cancer-specific gene requirements and the processes driving their requirement has hampered development of targeted therapeutic strategies for cancer. However, in the past five years significant progress has been made in the development of culture systems for patient cancers that allow unprecedented access to cancer- evolved molecular pathways and cellular phenotypes. Over the past three years, we have developed a strategy for defining the nature of gene requirements in patient cancer samples. Our approach integrates data from functional genetic screens in patient derived cancer stem cells with network models constructed from "cancer- omics" data sets to make gene requirement predictions. In proof of concept studies for Glioblastoma multiforme (GBM), an incurable form of brain cancer, we have demonstrated the existence of GBM-lethal genes, which when inhibited render patient GBM tumor cells sensitive to cellular stresses that arise as a consequence of cellular transformation. In this application w use this cancer-lethal prediction paradigm to address Provocative Question 8: Why do certain mutational events promote cancer phenotypes in some tissues and not others? We test the hypothesis that GBM-specific requirements for gene activities arise from one of three context-specific constraints: (a) the tissue of origin (i.e., neural-specific activity); (b) a GBM-specific evolution process; or (c) cellular transformation process in general. Our experimental approach will combine data from functional genetic screen in human GBM stem cells (of multiple subtypes) with pre-existing Bayesian network models for GBM and other cancers including, breast, lung, ovarian, and prostate (generated from The Cancer Genome Atlas patient data sets). If successful, these studies will reveal the extent and origin of GBM-specific requirements for gene activities in GBM patient samples. In addition to providing key insight into brain tumor biology, these studies will significantly aid in identifying new targeted therapeutic strategies fo GBM and other cancers with standard of care therapies suffering from poor therapeutic windows.