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: 7389439
• 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/7389439
• 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 Disease; 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; Purpose; Radioactivity; Radioimmunoassay; 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; 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.

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，这些受体可能是识别这些蛋白质胞外区域特殊特征的抗体的靶标。中枢神经系统受体可促进小细胞肺癌的生长，拮抗剂和抗体可抑制其生长。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，它也增加了开发针对残留和复发疾病的新的靶向疗法的可能性，并通过可视化标志物来直接监测这些治疗的效果(S)。目的/假设：本项目的目标是提供新的方法，将残留和复发的小细胞肺癌(SCLC)的检测和治疗联系起来。正在检验的假设是，小细胞肺癌表达的已识别的中枢神经系统受体将为连接检测、监测和治疗提供敏感和可靠的靶点。具体目标：目标是：(I)确定两种中枢神经系统受体在小细胞肺癌中的分布和丰度及其在这些肿瘤中的选择性表达；(Ii)完成针对一种中枢神经系统受体的单抗的研制并测试其结合特性；(Iii)从其中一种抗受体单抗中确定99mTechNe标记的Fabs的有效性，以成像在裸鼠体内生长的经典型(代表初发癌)和变异型(代表复发癌)小细胞肺癌作为实验动物；以及(Iv)评价所选择的单抗在无瘤小鼠体内摧毁和/或防止经典和变异形式的小细胞肺癌移植瘤生长的能力。使用抗体的成像和治疗将与使用无处不在的免疫球蛋白和DTPA-99TcHm的方法进行比较。FABS是由完整的抗体通过酶裂解产生的小结合片段。设计：这些研究将使用活体动物的全身扫描，以确定应该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。它们还将涉及测量小鼠肿瘤生长、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、Western分析和流式细胞术。与健康相关：该项目承诺产生广泛可用和敏感的方法，这些方法有可能将对大多数或全部小细胞肺癌患者的治疗和监测与有效检测残留肿瘤和复发疾病联系起来。这些方法与现有的检测方法如正电子发射计算机断层扫描(PET)结合使用，最终可能导致治疗复发小细胞肺癌的新的、更好的理论基础。每年约有42,000名新的小细胞肺癌患者，5年后的存活率为6%，新癌症标记物的识别为开发有效治疗这种致命疾病的诊断和治疗产品提供了独特的机会。目前，复发的小细胞肺癌没有治疗方法，患者通常在3到6个月内死于这种疾病。这项拟议的研究有望带来治疗小细胞肺癌的新的、成功的方法，从而提高患者的存活率。