Experimental Modeling of Human Breast Cancer in Mice

人类乳腺癌小鼠实验模型

基本信息

批准号：
7603107
负责人：
HALLGEIR RUI
金额：
$ 32.31万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-07 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7603107
关键词：
Adjuvant Antibodies Antineoplastic Agents Apoptotic Arts Biochemical Biology Breast Breast Cancer Cell Breast Cancer Model Cancer Patient Cancer cell line Cell Line Cell Survival Cells Cessation of life Clinic Clinical Clinical Treatment Clinical Trials Complement Data Development Differentiation and Growth Doxorubicin Endocrine Engineering Environment Epithelial Epithelial Cells Evaluation Expenditure Experimental Models Goals Government Growth Histology Homebound Persons Hormonal Hormones Human In Situ In Vitro Institution Laboratories Malignant Neoplasms Mammary gland Medical Medicine Methods Modeling Mus Neoplasm Metastasis Paclitaxel Pain Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phosphorylation Physiological Pituitary Hormones Postmenopause Pre-Clinical Model Preclinical Testing Premenopause Primary Neoplasm Prolactin Prolactin Receptor Protein Tyrosine Kinase Proteins RNA Interference Receptor Signaling Research Resources Role Serum Signal Pathway Signal Transduction Stimulus Testing Therapeutic Agents Tissue Microarray Tissues Transplantation Tumor Cell Line United States National Institutes of Health Woman Work antitumor agent antitumor drug autocrine base breast cancer diagnosis cancer cell cancer therapy clinical efficacy density drug candidate drug sensitivity drug testing efficacy testing expectation improved in vivo inhibitor/antagonist insight knock-down malignant breast neoplasm mouse model mutant novel pre-clinical prevent receptor response therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): Despite enormous expenditures and efforts by academic, government, and pharmaceutical institutions, most drugs that show promise against human breast cancer in preclinical testing in mice, fail to cure breast cancer in the clinic. There is a great need for improved drug response-predictive testing of human breast cancer in the preclinical setting to identify the best drug candidates. Based on novel insight gained in our laboratories, as a key first step we propose to correct the mouse endocrine environment to more adequately mimic the endocrine environment of breast cancer patients. Novel and independent insight from the two collaborating laboratories suggest that prolactin acts as a modulator of drug sensitivity in human breast cancer. Prolactin receptors are expressed, often at elevated levels, in a majority of human breast cancers. However, current mouse models are inadequate since mouse prolactin prevents activation of human prolactin receptors. Thus, current predictive testing of drugs against human breast cancer is performed on human breast cancer lines selected for growth under prolactin-free conditions. We will now test the role of prolactin as a modulator of breast cancer drug sensitivity and biology. For this study, a mouse model that expresses physiological levels of human prolactin has been genetically engineered for more accurate predictive testing of drugs on human breast cancer xenotransplants. The central hypothesis is that PRL receptor signaling, through its effects on mammary cell survival, growth, and differentiation, modulates sensitivity of breast cancer cells to anti-tumor agents. Consistent with this, we further hypothesize that mice, in which endogenous mouse prolactin has been replaced with physiological levels of human prolactin, will restore prolactin receptor signaling in human breast cancer xenotransplants and provide a more relevant endocrine environment for improved prediction of clinical responsiveness of breast cancer to therapeutic agents. Finally, we hypothesize that the hPRL expressing mice will allow us to establish new and transplantable breast cancer lines that more closely resemble primary breast human cancer than existing metastasis-derived tumor cell lines. If successful, the new mouse model would be available for testing of a broad number of human breast cancer drug candidates, with the potential for more reliable prediction of clinical efficacy. In addition, successful transplantation of primary breast cancer tissue with epithelial and stromal components will pave the road to a new personalized medicine approach to treatment of breast cancer patients. PUBLIC HEALTH RELEVANCE: Most drugs that work when tested on human breast cancer in mice, fail to cure breast cancer in humans. There is a great need to improve the ability to predict whether candidate breast cancer drugs will work in patients. To this end, we have developed a new mouse model with a hormone environment that more closely resembles that of breast cancer patients. We will test the hypothesis that the new mouse represents an improved preclinical model for more accurate predictive testing of breast cancer drug candidates.

描述（由申请人提供）：尽管学术，政府和制药机构的支出和巨额支出和努力，但大多数在小鼠临床前检查中对人类乳腺癌有望有望的药物，但在诊所无法治愈乳腺癌。在临床前环境中，非常需要改善对人类乳腺癌的药物反应预测性测试，以鉴定最佳的候选药物。基于在实验室中获得的新洞察力，作为关键的第一步，我们建议校正小鼠内分泌环境，以更充分地模仿乳腺癌患者的内分泌环境。来自两个合作实验室的新颖和独立的见解表明，催乳素是人类乳腺癌中药物敏感性的调节剂。在大多数人乳腺癌中，催乳素受体通常在较高的水平上表达。但是，当前的小鼠模型是不足的，因为小鼠催乳素可防止人催乳素受体的激活。因此，目前对针对人乳腺癌的药物进行的预测性测试是在无催乳素条件下选择用于生长的人类乳腺癌系。现在，我们将测试催乳素作为乳腺癌药物敏感性和生物学的调节剂的作用。在这项研究中，一种表达人催乳素生理水平的小鼠模型已经过基因设计，以对人类乳腺癌异种移植抗体的药物进行更准确的预测性测试。中心假设是PRL受体信号通过其对乳细胞存活，生长和分化的影响调节乳腺癌细胞对抗肿瘤剂的敏感性。与此相一致，我们进一步假设，内源性小鼠催乳素已被人催乳素取代的小鼠将恢复人类乳腺癌异种移植剂中催乳素受体信号传导，并提供更相关的内分泌环境，以改善对治疗症治疗药物乳腺癌临床响应的预测。最后，我们假设表达小鼠的HPRL将使我们能够建立新的和可移植的乳腺癌系，比现有转移源性肿瘤细胞系更类似于原发性乳腺癌。如果成功，新的小鼠模型将用于测试大量的人类乳腺癌候选者，并有可能更可靠地预测临床功效。此外，用上皮和基质成分成功移植原发性乳腺癌组织将为治疗乳腺癌患者治疗新的个性化医学方法铺平道路。公共卫生相关性：大多数对小鼠人类乳腺癌进行测试时起作用的药物，无法治愈人类的乳腺癌。非常需要提高预测候选乳腺癌药物是否在患者中起作用的能力。为此，我们开发了一种具有激素环境的新小鼠模型，该模型与乳腺癌患者更相似。我们将检验以下假设：新小鼠代表改进的临床前模型，以更准确地对乳腺癌药物的候选物进行预测性测试。