ENDOCRINE CANCER

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This proposal is designed to continue our in vivo and in vitro studies of three groups of diagnostic markers for hormone- producing tumors: 1) Peptides encoded by the calcitonin (CT) gene. The CT gene not only encodes CT, itself, but at least two additional peptides, CGRP (calcitonin-gene-related-peptide) and Katacalcin (PDN21). Each of these peptides if produced by medullary thyroid carcinoma, certain lung cancers,and other endocrine tumors. 2) Chromogranin A (CgA) and its related proteins and peptides. CgA is a protein that is present in many endocrine glands and is co-secreted with the resident hormones of those glands. It's tissue and serum concentration can thus serve as markers for a variety of eutopic and ectopic endocrine tumors. CgA may represent a family of proteins and peptides that have specificity for different endocrine cells. 3) Novel endocrine tumor markers defined by monoclonal antibodies and cDNA probes. Using monoclonal antibody and cDNA probes specific to endocrine tumors, we have identified at least four additional products of endocrine cancers that have potential as tumor markers. Two are defined by monoclonal antibodies to medullary thyroid carcinoma, one by a monoclonal antibody to pancreatic islet cells, and one by a cDNA to CgA under relaxed hybridization conditions. We propose to study the tissue specificity, biosynthesis, and secretion of these three groups of endocrine tumor markers. We have developed human endocrine cell lines that produce and secrete these substances. For these cell lines we have developed immunohistochemical procedures to determine the tissue specificity of the tumor markers, recombinant DNA methods to study their gene transcription, and immunoassay procedures to study their secretion. For clinical studies, we have developed immunohistology procedures to determine the tissue specificity of these tumor markers and immunoassay systems to study their secretion in patients with endocrine cancer. These studies should elucidate the mechanism that regulate the biosynthesis and secretion of our established and novel putative tumor markers by human endocrine cell lines. In addition, the studies should lead to the development of immunohistology and immunoassay procedures that can be clinically valuable in the classification, diagnosis, and management of ectopic hormone- producing tumors like lung cancer and eutopic hormone-producing tumors of essentially every endocrine cell type. In short, these studies should help to develop new tools for the biology and management of patients with endocrine cancer.