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

描述(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，绝经前的非洲裔美国女性的乳腺癌发病率明显高于高加索裔美国女性，而且在任何年龄段的死亡率都更高。报告显示，年轻的非裔美国人患上基底细胞样三阴性乳腺癌的几率更高。目前，还没有有效的分子疗法来治疗这种高度侵袭性的癌症，因此，患者的存活率很低。这项拟议的研究的主要意义是它专注于识别和测试治疗这种侵袭性的基底样样乳腺癌的新的翻译靶点。先前的研究表明，CD44的高表达是基底样乳腺癌中干细胞样、异种移植起始细胞的关键组成部分；因此，确定CD44在这些肿瘤起始细胞中的作用是开发靶向治疗的关键步骤。初步结果显示，与管腔型乳腺癌亚型相比，基底样型乳腺癌中CD44表达上调，并有独特的CD44变体表达。此外，初步研究发现了一种新的外毒素，通常与哺乳动物的肠道疾病有关，它选择性地结合高表达CD44的乳腺癌细胞，改变CD44信号转导并诱导细胞死亡。因此，本研究拟从功能上确定该毒素与CD44相互作用的机制，并确定其作为治疗CD44高表达的基底细胞样乳腺癌的可能性。在该方案的第一阶段，将使用绝对定量RT-PCR、流式细胞术和免疫组织化学方法在细胞系和原发乳腺癌样本中确定CD44的总水平和变异表达谱在管腔型和基底样型乳腺癌中的表达。这些信息将被用来确定毒素的目标细胞群体，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(目标1)。这项研究的第二阶段提出了初步的体内异种移植实验，这是翻译开发用于癌症治疗的毒素所必需的(目标2)。这项提案产生的数据将为未来提案提供基础，总体目标是开发新的靶向疗法，用于治疗侵袭性的基底样乳腺癌，特别是年轻的非裔美国女性。

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.