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

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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.