We propose to mesh the efforts of capable basic biologists exploring the mechanisms and markers of gastrointestinal epithelium transformation and differentiation with established clinical investigators attempting to define the diagnostic and therapeutic utility of conventional and new colorectal cancer phenotypes. This program will have the following goals: (1) improvement in the clinical utility of CEA and CEA-like markers by better definition of the metabolism and pharmacokinetics of shed glycoprotein; (2) definition of the biologic function of specific cell surface glycoproteins associated with colon and rectum cancers; (3) detailed biochemical analysis of the cell surface and cytoskeletal structures of colorectal cancer cells to determine molecular analogies between GI epithelial differentiation and transformation; (4) determination of relationships between phenotypes defined among colorectal cancers and gene products of oncogenes and proto-oncogenes known to be associated with human colorectal cancer and selected GI tumor model systems; (5) identification of new colorectal cancer cytoskeletal and cell surface phenotypes to define more useful markers of predominantly poorly differentiated gastrointestinal cancers; (6) application of new markers in clinical protocols to demonstrate in vivo targeting, serodiagnostic efficacy, and to monitor therapy. The themes that have consolidated these individual basic and clinical investigations are: (1) continuity with past accomplishments by Norman Zamcheck et al in defining the clinical utility of gastrointestinal tumor markers; (2) basic research and clinical interest in defining the mechanisms of synthesis, regulation, metabolism, and function of prototype and newly identified glycosylated GI tumor antigens; (3) a postulated relationship between GI epithelium differentiation and transformation phenotypes/genotypes; (4) an attempt to define a library of new GI epithelial differentiation markers by linkage to conventional morphologic categories of colon and rectum cancer differentiation and subsequent testing as differentiation markers applicable to normal GI epithelial maturation; and, most important (5) the establishment of efficient methods of transition from the basic biologic studies to appropriate clinical research protocols defining diagnostic and therapeutic utility of new markers in patients with colorectal cancer. Clinical progress in this disease will depend upon the kind of meshing of basic biologists and clinical researchers that this program project represents.
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