Evolution of cancer-specific molecular requirements for glioblastoma multiforme (

多形性胶质母细胞瘤癌症特异性分子要求的演变（

基本信息

批准号：
8534069
负责人：
Patrick Paddison
金额：
$ 17.66万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-20 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8534069
关键词：
Address Automobile Driving Behavior Brain Brain Neoplasms Breast Cancer Biology Cancer Patient Categories Cell Proliferation Cells Cellular Stress Computer Simulation Consensus Data Data Set Development Dose-Limiting Event Evolution Future Gene Targeting Genes Genetic Genetic Screening Genome Glioblastoma Goals Histocompatibility Testing Human Individual Knowledge Lethal Genes Lung Malignant Neoplasms Malignant neoplasm of brain Metric Modeling Molecular Nature Normal tissue morphology Ovarian Pathway Analysis Pathway interactions Patients Pattern Phenotype Process Prostate Sampling Stem cells System Testing The Cancer Genome Atlas Therapeutic Tissues Toxic effect Tumor Biology Tumor Subtype Validation Variant Work base brain cell cancer stem cell cancer type cell transformation cell type computer based statistical methods genetic profiling insight metaplastic cell transformation mouse model neoplastic cell network models new therapeutic target relating to nervous system screening self-renewal small hairpin RNA standard of care success therapeutic target tumor

项目摘要

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.

描述（由申请人提供）：在癌症生物学中，很明显，不同癌症类型对特定基因活性的要求可能存在很大差异。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。起源以及癌症发展本身的过程。我们目前对癌症特异性基因需求及其驱动过程缺乏了解，这阻碍了癌症靶向治疗策略的开发。然而，在过去五年中，癌症患者培养系统的开发取得了重大进展，使人们能够前所未有地了解癌症进化的分子途径和细胞表型。在过去的三年里，我们制定了一项策略来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根据“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。在针对多形性胶质母细胞瘤 (GBM)（一种无法治愈的脑癌）的概念验证研究中，我们证明了 GBM 致死基因的存在，当该基因被抑制时，患者 GBM 肿瘤细胞对细胞转化产生的细胞应激敏感。在此应用中，我们使用这种癌症致死预测范式来解决挑衅性问题 8：为什么某些突变事件会促进某些组织而不是其他组织中的癌症表型？我们测试了以下假设：GBM 对基因活动的特定要求来自三个特定环境限制之一：（a）起源组织（即神经特异性活动）； (b) GBM 特定的演化过程；或 (c) 一般细胞转化过程。我们的实验方法将把人类 GBM 干细胞（多种亚型）的功能遗传筛选数据与 GBM 和其他癌症（包括乳腺癌、肺癌、卵巢癌和前列腺癌）（由癌症基因组图谱患者生成）的现有贝叶斯网络模型相结合数据集）。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重要见解外，这些研究还将显着有助于确定 GBM 和其他治疗窗口较差的标准护理疗法的癌症的新靶向治疗策略。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impact of non-neoplastic vs intratumoural hepatitis B viral DNA and replication on hepatocellular carcinoma recurrence.

非肿瘤性与肿瘤内乙型肝炎病毒 DNA 和复制对肝细胞癌复发的影响。

DOI：
发表时间：
2016-09-27
期刊：
影响因子：
8.8
作者：
Wang, Qin;Lin, Luan;Yoo, Seungyeul;Wang, Wenhui;Blank, Sima;Fiel, M Isabel;Kadri, Hena;Luan, Wei;Warren, Leslie;Zhu, Jun;Hiotis, Spiros P
通讯作者：
Hiotis, Spiros P

Network-based differential gene expression analysis suggests cell cycle related genes regulated by E2F1 underlie the molecular difference between smoker and non-smoker lung adenocarcinoma.

基于网络的差异基因表达分析表明，E2F1 调控的细胞周期相关基因是吸烟者和非吸烟者肺腺癌之间分子差异的基础。