NMDA receptors in the diagnosis and treatment of breast cancer

NMDA受体在乳腺癌诊断和治疗中的应用

• 批准号: 7787905
• 负责人: WILLIAM G NORTH
• 金额: $ 17.18万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-07 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787905
• 关键词: Affinity; Affinity Chromatography; Alcohol or Other Drugs use; Animal Testing; Animals; Antibodies; Apoptotic; Behavior; Binding; Biopsy; Blinded; Brain; Breast; Breast Cancer Cell; Breast Cancer Treatment; Breast Fibrocystic Disease; Cancer Patient; Cancer cell line; Cells; Clinical; Cloning; DNA Sequence; Data; Detection; Development; Diagnosis; Diagnostic Imaging; Disease; Dose; Ductal; Effectiveness; Enzyme-Linked Immunosorbent Assay; Enzymes; Estrogens; Evaluation; Extracellular Domain; Fab Immunoglobulins; Flow Cytometry; Generations; Goals; Growth; Growth Factor; Health; IgG1; Image; Immunoglobulins; Immunohistochemistry; In Vitro; Individual; Investigation; Label; Lead; Legal patent; Libraries; Life; Lobular; MCF7 cell; MDA MB 231; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Measurement; Measures; Metastatic/Recurrent; Methods; Molecular; Monitor; Monoclonal Antibodies; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; Neoplasm Metastasis; Neuraxis; Normal tissue morphology; Nude Mice; Organ; Outcome; Pathology; Pathway interactions; Patients; Radioactivity; Receptor Activation; Recurrence; Recurrent disease; Relapse; Residual Tumors; Residual state; Reverse Transcriptase Polymerase Chain Reaction; Role; Scanning; Signal Transduction; Specificity; Spinal; Testing; Time; Tissue Microarray; Tissues; Tumor Volume; Tumor Weights; Weight; Xenograft procedure; base; design; effective therapy; follow-up; human tissue; imaging modality; immunoreactivity; in vivo; killings; malignant breast neoplasm; novel strategies; outcome forecast; prevent; public health relevance; receptor; response; selective expression; small hairpin RNA; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor xenograft; whole body imaging

DESCRIPTION (provided by applicant): Our data show expression of two receptors selectively found in the central nervous system (CNS) are very likely to be features common to all or most breast cancer (BC), and that these receptors can potentially be targeted by polyclonal and monoclonal antibodies recognizing special features in their extracellular domain. The CNS receptors promote growth of breast cancer that can be inhibited by antagonists and antibodies. Expression of such receptors therefore not only presents us with markers, for identifying tumor in breast biopsies, and for monitoring treatment of the disease(scanning for tumor response, metastases, residual tumor), but also raises the possibility to later develop new therapies. Objective/Hypothesis: The objective of this project is to provide new methods for the imaging and treatment of breast cancer (BC). The hypothesis being tested is that identified CNS receptors expressed by BC will provide sensitive and reliable targets for better detection, monitoring, and eventual treatment. Specific Aims: Goals are directed towards: (i) establishing the distribution and abundance in breast cancer of the two CNS receptors and their selective expression by these tumors; (ii) ascertaining the effectiveness of 99mTechnetium-labeled Fabs from available anti-receptor monoclonal antibodies to image estrogen responsive and estrogen-unresponsive BC grown in athymic mice as test animals; (iii) discerning the molecular pathways involved in tumor receptor activation and blockade; (iv) assessing the specificity of receptor blockade, and; (v) determining the effectiveness of a selected monoclonal antibody to destroy/prevent growth of estrogen-responsive and estrogen-unresponsive (triple-negative) BC grown in athymic mice. Imaging and treatment with antibodies will be compared with those using ubiquitous immunoglobulin. Fabs are small binding fragments generated from intact antibodies through enzyme cleavage. Design: These investigations will employ whole body scanning of the live animals for radioactivity that should be concentrated in the tumors, and later measurement of the levels of radioactivity in different tissues. They will also involve daily size measurements of treated tumors, affinity chromatography, immunohistochemistry of human tissues, RIA, ELISA, RT-PCR, cloning, and DNA sequencing, shRNA knockdown, Western analysis, pathology, and flow cytometry. Health Relatedness: This project promises the generation of widely available and sensitive methods that have the potential for identifying cancer in breast tissue, and monitoring treatments (evaluating tumor response, detecting residual tumor and recurrent disease, localizing metastases), in most, or all, individuals with BC. Employed approaches could also eventually lead to new and more effective treatments for patients suffering from recurrent BC. PUBLIC HEALTH RELEVANCE: Our project focuses on two receptor proteins, and should provide those treating breast cancer patients, with the prospect of new and precise methods for detecting disease in tissue biopsies at an earlier time, for detecting pockets of residual metastases, and for diagnosing relapse soon after a tumor recurs. Of more significance, it is also expected to eventually lead to effective new targeted treatments for most, or all, breast cancer. Such new treatments can then be directly and closely monitored for efficacy by visualizing the receptor protein markers on the tumor.

描述（由申请人提供）：我们的数据显示，在中枢神经系统（CNS）中选择性发现的两种受体的表达很可能是所有或大多数乳腺癌（BC）的共同特征，并且这些受体可能是多克隆和单克隆抗体识别其胞外域的特殊特征。中枢神经系统受体促进乳腺癌的生长，而乳腺癌的生长可以被拮抗剂和抗体抑制。因此，此类受体的表达不仅为我们提供了标记物，用于识别乳腺活检中的肿瘤，并用于监测疾病的治疗（扫描肿瘤反应、转移、残留肿瘤），而且还提高了以后开发新疗法的可能性。目的/假设：该项目的目的是为乳腺癌（BC）的成像和治疗提供新方法。正在测试的假设是，已鉴定的 BC 表达的 CNS 受体将为更好的检测、监测和最终治疗提供敏感且可靠的靶标。具体目标：目标针对： (i) 确定两种 CNS 受体在乳腺癌中的分布和丰度及其在这些肿瘤中的选择性表达； (ii) 确定来自可用抗受体单克隆抗体的 99m 锝标记的 Fab 对在作为测试动物的无胸腺小鼠中生长的雌激素反应性和雌激素无反应性 BC 进行成像的有效性； (iii) 辨别肿瘤受体激活和阻断所涉及的分子途径； (iv) 评估受体阻断的特异性，以及； (v)确定选定的单克隆抗体破坏/阻止在无胸腺小鼠中生长的雌激素反应性和雌激素无反应性（三阴性）BC生长的有效性。使用抗体的成像和治疗将与使用普遍存在的免疫球蛋白的成像和治疗进行比较。 Fab 是完整抗体通过酶裂解产生的小结合片段。设计：这些研究将对活体动物进行全身扫描，以查找应集中在肿瘤中的放射性，然后测量不同组织中的放射性水平。它们还将涉及治疗肿瘤的日常大小测量、亲和层析、人体组织的免疫组织化学、RIA、ELISA、RT-PCR、克隆和 DNA 测序、shRNA 敲低、Western 分析、病理学和流式细胞术。健康相关性：该项目有望产生广泛可用且敏感的方法，这些方法有可能识别乳腺组织中的癌症，并在大多数或全部情况下监测治疗（评估肿瘤反应、检测残留肿瘤和复发性疾病、定位转移）患有 BC 的人。所采用的方法最终还可能为患有复发性乳腺癌的患者带来新的、更有效的治疗方法。 公共健康相关性：我们的项目重点关注两种受体蛋白，应该为那些治疗乳腺癌患者提供新的、精确的方法的前景，以便更早地在组织活检中检测疾病、检测残留转移灶以及诊断肿瘤复发后很快就会复发。更重要的是，它还有望最终为大多数或所有乳腺癌带来有效的新靶向治疗。然后可以通过观察肿瘤上的受体蛋白标记来直接、密切地监测这种新疗法的疗效。