NMDA receptors in the diagnosis and treatment of small cell lung cancer.

NMDA 受体在小细胞肺癌诊断和治疗中的应用。

• 批准号: 7578934
• 负责人: WILLIAM G NORTH
• 金额: $ 17.99万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-07 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578934
• 关键词: Affinity; Affinity Chromatography; Animal Testing; Animals; Antibodies; Autopsy; Binding; Cancer Patient; Cancer cell line; Cell Line; Cells; Characteristics; Cloning; DNA Sequence; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Drug resistance; Early Diagnosis; Effectiveness; Enzyme-Linked Immunosorbent Assay; Enzymes; Evaluation; Extracellular Domain; Fab Immunoglobulins; Flow Cytometry; Generations; Goals; Growth; Health; Image; Immunoglobulin G; Immunoglobulins; Immunohistochemistry; In Vitro; Individual; Investigation; Label; Lead; Libraries; Life; Link; Location; Malignant Neoplasms; Measurement; Measures; Metastatic/Recurrent; Methods; Monitor; Monoclonal Antibodies; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; N-terminal; NMDA receptor A1; Neuraxis; Nude Mice; Organ; Outcome; Patients; Peptide Fragments; Positron-Emission Tomography; Property; Proteins; Radioactivity; Radionuclide Imaging; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; Research; Residual Tumors; Residual state; Reverse Transcriptase Polymerase Chain Reaction; Specificity; Staging; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Tissues; Tumor Volume; Tumor Weights; Tumor-Derived; Variant; base; cancer cell; design; effective therapy; human tissue; immunoreactivity; improved; lung small cell carcinoma; novel; polyclonal antibody; prevent; receptor; selective expression; tumor; tumor growth; tumor xenograft; uptake; whole body imaging

DESCRIPTION (provided by applicant): Backgound: 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 small-cell lung cancers (SCLC), and that these receptors can potentially be targeted by antibodies recognizing special features in the extracellular domain of these proteins. The CNS receptors promote growth of SCLC that can be inhibited by antagonists and antibodies. Expression of such receptors therefore presents us with markers for detecting residual tumor. However, more significantly, it also raises the possibility to develop new targeted therapies for residual and recurrent disease, and to directly monitor the efficacies of such treatments by visualizing the marker(s). Objective/Hypothesis: The objective of this project is to provide new methods that link detection and treatment of residual and recurrent small-cell lung cancer (SCLC). The hypothesis being tested is that identified CNS receptors expressed by SCLC will provide sensitive and reliable targets for linking detection, monitoring, and treatment. Specific Aims: Goals are directed towards: (i) establishing the distribution and abundance in small-cell lung cancer of the two CNS receptors and their selective expression by these tumors; (ii) completing the development of monoclonal antibodies against one CNS receptor and testing their binding properties (iii) determining the effectiveness of 99mTechnetium-labeled Fabs from one of these anti-receptor monoclonal antibodies to image a classical form (representing initial cancers) and a variant form (representing recurrent cancers) of SCLC grown in athymic mice as test animals; and (iv) evaluating the capacity of the selected monoclonal antibody to destroy and/or prevent growth of tumor xenografts of classical and variant forms of SCLC in athymic mice. Imaging and treatments with antibody will be compared with those using ubiquitous immunoglobulin and DTPA-99Technetium. 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 measuring tumor growth in mice, affinity chromatography, immunohistochemistry of human tissues, RIA, ELISA, RT-PCR, cloning, and DNA sequencing, Western analysis, and flow cytometry. Health Relatedness: This project promises the generation of widely available and sensitive methods that have the potential of linking effective detection of residual tumor and recurrent disease, with treatment and the monitoring of such treatment, in most, or all, individuals with small-cell lung cancer. Such methods, used in conjunction with detection methods already available such as PET, could eventually lead to a new and improved rationale for managing recurrent SCLC. With about 42,000 new SCLC patients per year and a survival rate of 6% after 5 year, the identification of novel cancer markers affords a unique opportunity to develop both diagnostic and therapeutic products to effectively treat this deadly disease. Currently, there is no treatment for recurrent SCLC and patients usually succumb to the disease in 3 to 6 months. The proposed research is expected to lead to new and successful approaches for managing SCLC, thereby leading to a higher survival rate of the patients.

描述（由申请人提供）：背景：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小细胞肺癌（SCLC）的共同特征，并且这些受体可以潜在地被识别这些蛋白质的细胞外结构域中的特殊特征的抗体靶向。CNS受体促进SCLC的生长，其可被拮抗剂和抗体抑制。因此，这些受体的表达为我们提供了检测残留肿瘤的标志物。然而，更重要的是，它还提高了开发针对残留和复发疾病的新靶向疗法的可能性，并通过可视化标记物直接监测此类治疗的疗效。目的/假设：该项目的目的是提供新的方法，将残留和复发的小细胞肺癌（SCLC）的检测和治疗联系起来。正在测试的假设是，确定的CNS受体表达的小细胞肺癌将提供敏感和可靠的目标，连接检测，监测和治疗。具体目标：目标是：（i）确定两种CNS受体在小细胞肺癌中的分布和丰度以及它们在这些肿瘤中的选择性表达;（ii）完成针对一种CNS受体的单克隆抗体的开发并测试它们的结合特性（iii）确定来自这些抗受体单克隆抗体之一的99m锝标记的Fab对经典形式成像的有效性在一个实施方案中，本发明提供了一种方法，该方法包括：（i）评估在作为测试动物的无胸腺小鼠中生长的SCLC的典型形式（代表初始癌症）和变体形式（代表复发性癌症）的单克隆抗体;以及（iv）评估所选单克隆抗体破坏和/或预防无胸腺小鼠中SCLC的典型形式和变体形式的肿瘤异种移植物生长的能力。将使用抗体的成像和治疗与使用泛在免疫球蛋白和DTPA-99锝的成像和治疗进行比较。Fab是通过酶切割由完整抗体产生的小结合片段。设计图：这些研究将采用活体动物全身扫描，以确定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。他们还将涉及测量小鼠肿瘤生长，亲和层析，人体组织免疫组织化学，RIA，ELISA，RT-PCR，克隆和DNA测序，Western分析和流式细胞术。健康相关性：该项目有望产生广泛可用的和敏感的方法，这些方法有可能将残留肿瘤和复发性疾病的有效检测与大多数或所有小细胞肺癌患者的治疗和这种治疗的监测联系起来。这些方法与现有的检测方法（如PET）结合使用，最终可能导致管理复发性SCLC的新的和改进的理由。每年约有42，000名新的SCLC患者，5年后的生存率为6%，新癌症标志物的鉴定为开发诊断和治疗产品提供了独特的机会，以有效治疗这种致命的疾病。目前，对于复发性SCLC没有治疗方法，患者通常在3至6个月内死于该疾病。这项研究有望为SCLC的治疗带来新的成功方法，从而提高患者的生存率。