Epigenetic changes and phenotype-specific therapeutic strategies in breast cancer

乳腺癌的表观遗传变化和表型特异性治疗策略

基本信息

批准号：
8007544
负责人：
ANDREA Hope BILD
金额：
$ 16.87万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-05 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8007544
关键词：
Adenoviruses Animal Model Appearance Automobile Driving Biological Biological Assay Biological Models Breast Cancer Cell Cancer Patient Cancer cell line Cell Culture Techniques Cell Line Chromatin Clinical Trials Complex Cultured Tumor Cells DNA Methylation DNA Methyltransferase DNA Methyltransferase Inhibitor DNA Microarray Chip DNA Modification Methylases Data Data Set Development Diagnostic Neoplasm Staging Disease Doxorubicin Drug Delivery Systems Drug effect disorder ERBB2 gene Epigenetic Process Epithelial Cells Event Family member Gene Expression Gene Expression Profile Gene Silencing Genes Genetic Genomics Goals Heterogeneity Histone Deacetylase Histone Deacetylation Human Immunocompromised Host Implant In Vitro Individual Interdisciplinary Study Language Link Malignant Neoplasms Mammary gland Measures Mediating Microarray Analysis Molecular Molecular Profiling Mus Mutation Oncogenic Pathway interactions Patients Pattern Pharmaceutical Preparations Phenotype Population Proliferating Regimen Research Research Personnel Role Seminal Series Signal Pathway Specificity Study models System Systems Biology Testing Therapeutic Therapeutic Uses Time Translating Treatment Efficacy Tumor Biology Tumor stage Work Xenograft Model Xenograft procedure anticancer research base cancer therapy chemotherapeutic agent clinical application drug sensitivity drug testing efficacy testing genetic analysis high risk in vivo in vivo Model inhibitor/antagonist innovation insight malignant breast neoplasm molecular phenotype mouse model novel novel strategies novel therapeutic intervention overexpression pre-clinical response small molecule tumor tumor growth tumor initiation tumor progression tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is a heterogeneous disease. A significant challenge in the development and testing of new therapies is determining which tumors a drug will target. Initial studies with a novel class of small molecule inhibitors of epigenetic pathways show therapeutic responsiveness in some breast cancers. Here, we propose to investigate the epigenetic changes that underlie diverse molecular phenotypes of breast cancer whose expression patterns have been previously considered on a global scale. We hope to identify which molecular phenotypes of breast cancer will be targeted by specific epigenetic pathway inhibitors. In this proposal, we will activate different epigenetic pathways in normal human mammary epithelial cells using adenoviruses carrying six different histone deacetylase (HDAC) or DNA methyltransferase (DNMT) family member genes to define six pathway expression signatures, characterized by system-wide patterns of activated and silenced genes. A set of over 1800 breast cancers, grouped by molecular phenotype (e.g. basal, luminal), will be queried for each of the six epigenetic pathway signatures to discover the specific epigenetic pathways that are deregulated in each phenotype. Next, we will determine which drugs best treat different phenotypes of breast cancer. Cell lines representing different molecular phenotypes of breast cancer will be treated with six different HDAC and DNMT inhibitors. The association of drug response to molecular phenotype in vitro will be used to predict tumor response in vivo. To do this, we will use fresh human tumors, classified by microarray analysis and orthotopically implanted in immunocompromised mice, to create a panel of tumor-specific xenograft models that represent the most aggressive molecular phenotypes of breast cancer: basal, ERBB2-overexpressing, and highly proliferating luminals. We will test the same six HDAC and DNMT inhibitors on the mouse models and measure how well they and a conventional chemotherapeutic agent (doxorubicin) inhibit tumor growth, verifying the in vitro predictions in an in vivo model system. We hope that our results will provide preclinical evidence for the initiation of a human trial that employs a more focused approach to the use of small molecule inhibitors of epigenetic processes by defining specific phenotypes of breast cancer that a given drug should target rather than testing that drug on all breast cancers. This proposal should demonstrate how tumor biology and genomic signatures can be translated into strategies for personalized cancer treatment.

描述（由申请人提供）：乳腺癌是一种异质疾病。新疗法开发和测试的一个重大挑战是确定药物将靶向哪些肿瘤。对表观遗传途径的新型小分子抑制剂的初步研究表明，某些乳腺癌的治疗反应性。在这里，我们建议研究乳腺癌的各种分子表型的表观遗传变化，这些变化先前已经在全球范围内考虑过其表达模式。我们希望确定哪些分子表型将由特定的表观遗传途径抑制剂靶向。在该提案中，我们将使用载有六种不同组蛋白脱乙酰基酶（HDAC）或DNA甲基转移酶（DNMT）家族成员基因的腺病毒在正常的人类乳腺上皮细胞中激活不同的表观遗传途径，以定义六个途径表达签名，以系统范围的模式表征，并以系统范围的模式表征活性基因的系统。一组由分子表型（例如基底，腔内）分组的1800多种乳腺癌将针对六个表观遗传途径标志中的每一个中的每个癌症进行查询，以发现在每种表型中均受过管制的特定表观遗传途径。接下来，我们将确定哪些药物最好治疗乳腺癌的不同表型。代表不同分子表型的乳腺癌的细胞系将用六种不同的HDAC和DNMT抑制剂治疗。药物对分子表型的反应在体外将用于预测体内肿瘤反应。为此，我们将使用新鲜的人类肿瘤，该肿瘤通过微阵列分析和原位植入免疫功能低下的小鼠进行分类，以创建一组肿瘤特异性的异种移植模型，这些模型代表了乳腺癌的最具侵略性的分子表型：基础，ERBB2过度表达和高度繁殖的文论。我们将在小鼠模型上测试相同的六个HDAC和DNMT抑制剂，并测量它们和常规化学治疗剂（阿霉素）抑制肿瘤生长，从而验证体内模型系统中的体外预测。我们希望我们的结果将为启动人类试验提供临床前证据，该试验采用更集中的方法来使用表观遗传过程的小分子抑制剂，通过定义特定的乳腺癌表型，即给定的药物应靶向而不是对所有乳腺癌进行测试。该建议应证明如何将肿瘤生物学和基因组特征转化为个性化癌症治疗的策略。