Development of a novel targeted-therapy for treatment of basal-like breast cancer

开发治疗基底样乳腺癌的新型靶向疗法

基本信息

批准号：
8551659
负责人：
Jodie Michelle Fleming
金额：
$ 9.78万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
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：
2012-09-26 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8551659
关键词：
Address Affect Affinity African American Age Apoptosis Architecture Binding Biological Assay Biopsy Blocking Antibodies Breast Breast Cancer Cell Breast Carcinoma CD44 gene Cancer Patient Cancer cell line Cell Culture Techniques Cell Cycle Cell Death Cell Line Cell Polarity Cell Surface Receptors Cells Cessation of life Clostridium perfringens Collecting Cell Data Detection Development Disease Dose Enteral Estrogen receptor negative Evaluation Excision Exotoxins Flow Cytometry Foundations Future Goals Image Imaging technology Immunohistochemistry In Vitro Incidence Life Malignant Neoplasms Mammalian Cell Mammals Measures Mediating Microscopy Molecular Molecular Profiling Morphology Mus Necrosis Neoplasm Metastasis Normal Cell Nuclear Outcome Patients Phase Phenotype Population Premenopause Proteins Reaction Time Reporter Reporting Resistance Reverse Transcriptase Polymerase Chain Reaction Role Sampling Signal Transduction Small Interfering RNA Target Populations Technology Testing Therapeutic Tissues Toxin Tumor Markers Tumor Tissue Up-Regulation Variant Woman Work Xenograft procedure angiogenesis base cancer cell cancer diagnosis caucasian American extracellular improved in vivo indexing inhibitor/antagonist innovation killings malignant breast neoplasm migration mortality neoplastic cell new therapeutic target novel polarized cell research study response stem therapeutic target tool triple-negative invasive breast carcinoma tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the most commonly diagnosed cancer in US women. Notably, premenopausal African- American women have a significantly higher incidence rate of breast cancer compared to Caucasian- American, and a higher mortality rate at any age. Reports show young African-American patients have a higher incidence of the basal-like "triple-negative" breast cancer. Currently, no effective molecular therapies exist for this highly aggressive cancer and, consequently, patient survival is poor. The primary significance of the proposed study is its focus on identifying and testing novel translational targets for treatment of this aggressive, basal-like breast cancer. Previous studies show high CD44 expression is a critical component of stem-like, xenograft-initiating cells in basal-like breast cancer; therefore, defining the role of CD44 in these tumor-initiating cells is a essential step in developing targeted therapeutics. Preliminary results show an upregulation of CD44, and unique CD44 variant expression, in basal-like breast cancer compared to luminal breast cancer subtypes. Additionally, preliminary studies have identified a novel exotoxin, commonly associated with enteric diseases of mammals, that selectively binds high CD44 expressing breast cancer cells, alters CD44 signaling and induces cell death. Therefore, this proposal intends to functionally determine the mechanisms of this toxin's interaction with CD44 and to determine its potential as a therapy for high CD44 expressing, basal-like breast cancer. During the first phase of this proposal, the total levels and variant expression profile of CD44 wil be defined in luminal and basal-like breast cancer phenotypes using absolute quantitative RT-PCR, flow cytometry and immunohistochemistry in cell lines and primary breast cancer samples. This information will be used to define the toxin's target population of cells, and correlate the sensitivity of cancer cells to toxin exposure with CD44 expression and cancer phenotypes (Aim 1). The second phase of this study proposes the initial in vivo xenograft experiments necessary for translational development of the toxin for cancer therapeutics (Aim 2). The data generated from this proposal will provide the foundation of future proposals with the overall goal to develop novel targeted therapies for treatment of aggressive, basal-like breast cancer, particularly in young African-American women.

描述（由申请人提供）：乳腺癌是美国女性最常见的癌症。值得注意的是，与白种人的美国妇女相比，绝经前非洲裔美国妇女的乳腺癌发病率明显更高，并且在任何年龄段的死亡率更高。报告显示，年轻的非裔美国人患者的基础样“三阴性”乳腺癌发生率更高。目前，这种高度侵略性的癌症尚无有效的分子疗法，因此患者的生存率很差。拟议的研究的主要意义是它的重点是识别和测试新的翻译目标，以治疗这种侵略性的基础样乳腺癌。先前的研究表明，CD44的高表达是基础类乳腺癌中类茎状的，异种移植细胞的关键成分。因此，定义CD44在这些肿瘤发射细胞中的作用是发展靶向治疗剂的重要步骤。初步结果表明，与腔内乳腺癌亚型相比，基底样乳腺癌的CD44和独特的CD44变异表达的上调。此外，初步研究已经确定了一种新型的外毒素，通常与哺乳动物的肠道疾病相关，该毒素有选择地结合表达乳腺癌细胞的高CD44，改变CD44信号传导并诱导细胞死亡。因此，该提案打算在功能上确定这种毒素与CD44相互作用的机制，并确定其作为高CD44表达基础类似基础乳腺癌的疗法的潜力。在该提案的第一阶段中，使用绝对定量的RT-PCR，流式细胞术和免疫组织化学在细胞系和原发性乳腺癌样品中，将在腔和基础乳腺癌表型中定义CD44的总水平和变异表达谱。该信息将用于定义毒素的细胞靶群，并将癌细胞对毒素暴露的敏感性与CD44表达和癌症表型相关联（AIM 1）。这项研究的第二阶段提出了用于癌症治疗毒素的转化开发所需的初始体内异种移植实验（AIM 2）。该提案产生的数据将为未来的提案提供基础，其总体目标是开发新颖的靶向疗法，以治疗侵略性的基础乳腺癌，尤其是在非裔美国人的年轻妇女中。