MUC-1 related cancer immunity: determinants and predictive significance

MUC-1 相关癌症免疫：决定因素和预测意义

• 批准号: 7455073
• 负责人: DANIEL William CRAMER
• 金额: $ 27.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-18 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7455073
• 关键词: Adenocarcinoma; Affect; Antibodies; Biological Assay; Blood specimen; Breast; CA-15-3 Antigen; Cell Membrane Proteins; Cellular Immunity; Data; Development; Diagnosis; Epithelial; Epithelial Cells; Epitopes; Event; Family; Family member; Fracture; Glycoproteins; Goals; Human; Immune; Immune response; Immune system; Immunity; Individual; Inflammation; Intrauterine Devices; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Medical; Memory; Molecular Weight; Mucin-1 Staining Method; Mucins; Nested Case-Control Study; Nurses' Health Study; Operative Surgical Procedures; Ovary; Performance; Placement; Plasma; Play; Predictive Value; Pregnancy; Prospective Studies; Risk; Role; Series; Specimen; Staging; Testing; Tissues; Translating; Tubal Ligation; Vaccines; Woman; base; cancer cell; cancer risk; case control; cohort; immunogenic; injury and repair; mastitis; member; novel; outcome forecast; prevent; prospective; reproductive; response; tumor

DESCRIPTION (provided by applicant): Human mucin (MUC) family member, MUC1, is a transmembrane glycoprotein expressed in low levels by normal, primarily, epithelial cells and high levels by cancer cells. Most epithelial adenocarcinomas, including those from the breast and ovary, over-express MUC1 and, more importantly, may promote anti-MUC1 antibodies, which correlate with more favorable prognosis. By extension, we hypothesized that the risk for cancer might be reduced by pre-existing MUC1-specific immunity and assembled persuasive cross-sectional and case-control data, which suggest that various medical and reproductive events, including breast mastitis, IUD use, tubal ligation, and bone fracture may predict the presence of anti-MUC1 antibodies and lower ovarian cancer risk. To validate these "retrospective" observations, we now propose a prospective study with three aims. Under aim 1, we will identify women either before or at the earliest stages of events that may affect MUC1 immunity and document changes in humoral and cellular immune responses related to MUC1. Under aim two, we will collect (pre-operative) blood specimens from women with ovarian cancer prior to any therapy to identify similarities or differences between tumor-generated immunity (both humoral and cellular) and the immunity that may be generated by the medical and reproductive events studied in aim 1. A goal of these analyses will be to identify the epitopes of MUC1 that are immunogenic in this setting and the types of immune responses generated in order that we may refine the assays used for measuring anti- MUC1 antibodies in aim 3. Under this aim, we will perform a nested case-control study within the Nurses Health Study (NHS) to assess directly the predictive value of anti-MUC1 antibodies many years prior to the development of ovarian cancer. We will select NHS cohort members with a plasma specimen available at least 4 years before they developed ovarian cancer and matched controls and measure anti-MUC1 antibodies to determine actual, rather than inferred, predictive value of antibodies using prospective epidemiologic data. The findings of our study could provide the basis for developing a safe cancer- preventing vaccine for ovarian cancer and perhaps other MUC1-expressing tumors.

描述（由申请人提供）：人粘蛋白（MUC）家族成员MUC1是一种跨膜糖蛋白，在正常的主要上皮细胞中低水平表达，在癌细胞中高水平表达。大多数上皮性腺癌，包括来自乳腺癌和卵巢的腺癌，过度表达 MUC1，更重要的是，可能会促进抗 MUC1 抗体的产生，这与更良好的预后相关。通过扩展，我们假设预先存在的 MUC1 特异性免疫力可能会降低患癌症的风险，并收集了有说服力的横断面和病例对照数据，这些数据表明各种医疗和生殖事件，包括乳腺炎、宫内节育器的使用、输卵管结扎和骨折，可以预测抗 MUC1 抗体的存在并降低卵巢癌风险。为了验证这些“回顾性”观察，我们现在提出一项具有三个目标的前瞻性研究。根据目标 1，我们将在可能影响 MUC1 免疫的事件之前或最早阶段识别女性，并记录与 MUC1 相关的体液和细胞免疫反应的变化。根据目标二，我们将在任何治疗之前收集卵巢癌女性的（术前）血液样本，以确定肿瘤产生的免疫（体液和细胞）与目标 1 中研究的医学和生殖事件可能产生的免疫之间的相似性或差异。这些分析的目标是确定在这种情况下具有免疫原性的 MUC1 表位以及免疫反应的类型 生成的目的是为了我们可以改进目标 3 中用于测量抗 MUC1 抗体的测定方法。根据这个目标，我们将在护士健康研究 (NHS) 内进行嵌套病例对照研究，以直接评估抗 MUC1 抗体在卵巢癌发生前许多年的预测价值。我们将选择 NHS 队列成员，他们在患卵巢癌前至少 4 年获得血浆样本，并匹配对照，并测量抗 MUC1 抗体，以使用前瞻性流行病学数据确定抗体的实际预测价值，而不是推断的预测价值。我们的研究结果可以为开发针对卵巢癌和其他表达 MUC1 的肿瘤的安全癌症疫苗提供基础。