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

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，并且这些受体可能被识别这些蛋白胞外结构域特殊特征的抗体靶向。中枢神经系统受体促进SCLC的生长，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余肿瘤的标记。然而，更重要的是，它也提高了开发针对残留和复发疾病的新靶向治疗的可能性，并通过可视化标记物直接监测这些治疗的疗效。目的/假设：本项目的目的是为残余和复发小细胞肺癌（SCLC）的检测和治疗提供新的方法。正在验证的假设是，经鉴定的SCLC表达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。具体目的：目的是：(1)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克隆抗体的开发并测试其结合特性（iii）确定这些抗受体单克隆抗体之一的99m锝标记fab对胸腺小鼠作为实验动物生长的SCLC的经典形式（代表初始癌症）和变体形式（代表复发癌症）的成像效果；（iv）评估所选单克隆抗体在胸腺小鼠中破坏和/或阻止经典和变异形式SCLC肿瘤异种移植物生长的能力。将抗体与泛在免疫球蛋白和DTPA-99Technetium的成像和治疗进行比较。fab是由完整抗体通过酶裂解产生的小结合片段。设计：这些调查将对活体动物进行全身扫描，寻找应该集中在肿瘤中的放射性物质，然后测量不同组织中的放射性水平。他们还将包括测量小鼠肿瘤生长，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。健康相关性：该项目有望产生广泛可用和敏感的方法，这些方法有可能将残余肿瘤和复发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，最终可能会为治疗复发性SCLC提供一种新的改进的理论依据。每年约有42,000例SCLC新患者，5年后的生存率为6%，新的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疾病。目前，没有治疗复发性SCLC的方法，患者通常在3至6个月内死亡。这项研究有望为SCLC的治疗带来新的和成功的方法，从而提高患者的生存率。

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.