Mouse Models of Metastatic Triple-Negative Breast Cancer for Therapeutic Testing

用于治疗测试的转移性三阴性乳腺癌小鼠模型

基本信息

批准号：
8903957
负责人：
CHARLES M. PEROU
金额：
$ 58.86万
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：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903957
关键词：
Accounting Address African American Biological Assay Breast Breast Cancer Model Breast Cancer Patient Cancer Etiology Cancer cell line Caring Cell Line Cells Cessation of life Chemotherapy-Oncologic Procedure Clinic Clinical Complex Mixtures Development Disease Distant Drug resistance ERBB2 gene Estrogen Receptors Etiology Experimental Models Extravasation Fatty acid glycerol esters Frequencies Gene Expression Profiling Genes Genetic Engineering Genetically Engineered Mouse Genomics Goals Heterogeneity Human Immune Immune system Immunocompromised Host In complete remission Label Lentivirus Vector Luciferases Lung Malignant Neoplasms Mammary gland Measurement Mesenchymal Metastatic to Minor Modeling Mus Neoadjuvant Therapy Neoplasm Metastasis Organ Outcome Pathway interactions Patients Phenotype Population Preclinical Testing Primary Neoplasm Progesterone Receptors Property Proteins Regimen Reporter Residual Tumors Resistance Role Shapes Site Structure of parenchyma of lung Testing Therapeutic Therapeutic Intervention Transplantation Treatment Efficacy Tumor Biology United States Woman Xenograft Model Xenograft procedure base burden of illness cancer therapy cancer type cell type cellular transduction chemotherapy effective therapy efficacy testing in vivo in vivo Model malignant breast neoplasm mortality mouse model non-invasive imaging novel outcome forecast pre-clinical preclinical study public health relevance response therapeutic target transcriptome sequencing treatment effect treatment response triple-negative invasive breast carcinoma tumor tumor xenograft

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 highly metastatic, with most patients who succumb to this disease dying of complications caused by their metastatic disease burden. Most preclinical studies of metastasis, however, study the dissemination and colonization of metastasis, and have failed to focus on the treatment of established metastases. The overall goal of our proposed studies, therefore, is to utilize preclinical Genetically Engineered (GEM) and Patient Derived Xenografts (PDX) models of TNBC to determine the efficacy of standard-of-care chemotherapy regimens for the treatment of established metastatic disease. Specifically, these studies will uniquely compare the therapeutic response of TNBCs in their orthotopic site versus the response of established lung metastases, both in immunocompromised models and those with an intact immune system. Recent technological advances using lentiviral vectors allow the efficient introduction of fluorescent and bioluminescent markers into primary tumors to facilitate both non-invasive imaging of metastases as well as re-isolation of transduced cells following treatment for detailed genomic analyses. The proposed therapeutic regimens have been chosen based upon their known efficacy for the treatment of primary TNBC disease in humans. In addition we will also examine the frequency and biology of Tumor Initiating Cells within these TNBC models, and determine if and how these TIC properties change according to microenvironment, and according to treatment. Because metastases are culpable for >90% of cancer-associated mortality, truly efficacious anti-metastatic therapies are desperately needed and our preclinical studies, therefore, should provide a new paradigm for testing these therapies.

描述（由申请人提供）：三阴性乳腺癌（TNBC）如果被视为其自身疾病，将成为美国女性癌症死亡的第五或第六大原因。这些患者的唯一治疗选择是多药治疗。 TNBC 肿瘤在化疗敏感性方面存在很大差异，TNBC 也具有高度转移性，大多数死于这种疾病的患者死于其转移性疾病负担引起的并发症。然而，研究转移的传播和定植，并未能关注已形成转移的治疗。因此，我们提出的研究的总体目标是利用临床前基因工程（GEM）和患者来源的异种移植物（PDX）。）TNBC 模型，以确定标准化疗方案治疗已确定转移性疾病的疗效。具体来说，这些研究将独特地比较 TNBC 的治疗反应。在免疫功能低下模型和具有完整免疫系统的模型中，原位位点与已建立的肺转移瘤的反应相比，使用慢病毒载体的最新技术进步允许将有效的荧光和生物发光标记物引入原发性肿瘤中，以促进转移瘤的非侵入性成像。以及在治疗后重新分离转导细胞以进行详细的基因组分析。所建议的治疗方案是根据其治疗人类原发性 TNBC 疾病的已知功效而选择的。肿瘤起始细胞在这些 TNBC 模型中的频率和生物学特性，并确定这些 TIC 特性是否以及如何根据微环境和治疗而变化。因为转移是导致 > 90% 的癌症相关死亡率的原因，所以真正有效的抗转移疗法。迫切需要这些疗法，因此，我们的临床前研究应该为测试这些疗法提供新的范例。