Therapeutic Targeting of Breast Cancer Tumor Initiating Cells

乳腺癌肿瘤起始细胞的治疗靶向

基本信息

批准号：
8963843
负责人：
CHARLES M. PEROU
金额：
$ 40.69万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2010-03-17 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8963843
关键词：
Accounting Affect African American Automobile Driving Basal Cell Behavior Breast Breast Cancer Patient Breast Fat Pad Cancer Etiology Cell Line Cells Cessation of life Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Mixtures Disease Distant Drug resistance ERBB2 gene Epigenetic Process Epithelial Epithelial Cells Estrogen Receptors Etiology Fatty acid glycerol esters Frequencies Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Determinism Genetically Engineered Mouse Genomics Heterogeneity Human Immunocompromised Host In Vitro Injection of therapeutic agent Knock-out Label Luciferases Lung Malignant Neoplasms Mesenchymal Minor Modeling Mus Neoplasm Metastasis Operative Surgical Procedures Outcome Pathway interactions Patients Phenotype Primary Neoplasm Progesterone Receptors Proteins RNA Sequences Relative (related person)Reporter Resistance Signal Pathway Site TP53 gene Tail Testing Therapeutic Therapeutic Intervention Time Transplantation United States Veins Woman Xenograft Model Xenograft procedure base cancer therapy cancer type cell type chemotherapy effective therapy efficacy testing human NFIB protein in vivo in vivo Model malignant breast neoplasm neoplastic cell notch protein public health relevance response standard of care therapeutic target transcription factor transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor xenograft

Accounting Affect African American Automobile Driving Basal Cell Behavior Breast Breast Cancer Patient Breast Fat Pad Cancer Etiology Cell Line Cells Cessation of life Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Mixtures Disease Distant Drug resistance ERBB2 gene Epigenetic Process Epithelial Epithelial Cells Estrogen Receptors Etiology Fatty acid glycerol esters Frequencies Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Determinism Genetically Engineered Mouse Genomics Heterogeneity Human Immunocompromised Host In Vitro Injection of therapeutic agent Knock-out Label Luciferases Lung Malignant Neoplasms Mesenchymal Minor Modeling Mus Neoplasm Metastasis Operative Surgical Procedures Outcome Pathway interactions Patients Phenotype Primary Neoplasm Progesterone Receptors Proteins RNA Sequences Relative (related person)Reporter Resistance Signal Pathway Site TP53 gene Tail Testing Therapeutic Therapeutic Intervention Time Transplantation United States Veins Woman Xenograft Model Xenograft procedure base cancer therapy cancer type cell type chemotherapy effective therapy efficacy testing human NFIB protein in vivo in vivo Model malignant breast neoplasm neoplastic cell notch protein public health relevance response standard of care therapeutic target transcription factor transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor xenograft

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项目摘要

DESCRIPTION (provided by applicant): Triple Negative Breast Cancers (TNBC), if considered its own disease, would rank as the fifth or sixth leading cause of cancer deaths in women in the USA. The only treatment option for these patients is multi-agent chemotherapy, and TNBC tumors are highly variable in terms of their chemotherapy sensitivity. TNBC is also known to be biologically heterogeneous, with multiple possible subtypes present. We hypothesize that much of this apparent heterogeneity actually represents cellular plasticity, and that some forms of heterogeneity can actual morph from one form into another; for example, in vitro and in vivo results show that within basal-like cell lines, claudin-low-like cells exist and can inter-convert nto the more differentiated basal-like epithelial state. We propose to test this plasticity hypothesis using in vivo models by identifying some of the genetic determinants that drive cells into the basal-like state (which is more chemotherapy sensitive), and that maintain TICs in basal-like cancers using both genetically engineered mouse (GEM) and patient derived xenograft (PDX) models. In addition, we will compare the response to standard of care therapies in the primary tumor versus a metastatic site (i.e. lung), and evaluate changes in TICs using unique signaling pathway-based reporters.

描述（由适用提供）：如果被认为是自身的疾病，三重阴性乳腺癌（TNBC）将被评为美国女性癌症死亡的第五或第六主要原因。这些患者的唯一治疗选择是多药化疗，而TNBC肿瘤在化学疗法敏感性方面的变化很大。 TNBC在生物学上也是异质性的，存在多种可能的亚型。我们假设这种明显的异质性实际上代表了细胞的可塑性，并且某些形式的异质性实际上可以从一种形式变为另一种形式。例如，体外和体内结果表明，在基本样细胞系中，存在claudin-low-like细胞，并且可以转化更为区分的基本样上皮状态。我们建议使用体内模型来检验这种可塑性假说，通过识别一些将细胞驱动到基本状态（更敏感的化学疗法）的遗传确定剂，并使用一般工程的小鼠（GEM）和耐心的衍生Xenograft（PDX）模型维持基本类似基本的癌症的TIC。此外，我们将比较原发性肿瘤与转移性部位（即肺）中护理疗法的反应，并使用基于唯一的信号途径的记者评估抽动的变化。