This proposal is to extend the investigators' previous studies of the biosynthesis, molecular biology, structure, and immunology of pancreatic cancer mucins. Pancreatic tumors frequently exhibit alterations in mucin gene expression, providing both diagnostic and therapeutic opportunities. Currently, however, knowledge of mucin peptide and carbohydrate structure is incomplete and even less is known about the mechanisms that regulate mucin biosynthesis and release. This information could be applied in several ways including the rational design of novel tumor markers, the enhancement of the effectiveness of mucin-directed antibodies, and the identification of potential targets for therapeutic intervention. In the past funding period they have characterized mucin carbohydrate antigen structure and identified the associated mucin polypeptides. They have also determined that MUC3 is an important component of pancreatic cancer mucin and made significant strides towards obtaining the complete sequence of this large mucin. In other work, the investigators have identified conditions and pharmacological agents capable of modulating mucin gene expression in pancreatic cancer cells and have shown that a human-mouse chimera of Nd2 antibody is an effective agent for the identification of pancreatic tumors. In the upcoming funding period they will continue their efforts in each of these areas. Studies on the biosynthesis of mucins will focus on identifying chemicals or peptides capable of elevating mucin expression and release. Studies on the molecular biology of mucins will focus on: 1) determining the complete cDNA sequence of MUC3 and 2) characterizing the regulation of the MUC3 gene. Studies on the structure of pancreatic cancer mucins will concentrate on: 1) determining the epitope of Nd2 antibody; 2) determining the structures of mucin oligosaccharides; and 3) characterizing pancreatic cancer cell binding to E-, L-, and P-selectins. Studies on the immunology of mucins will focus on: 1) increasing the effectiveness of Nd2 immunoconjugates; 2) producing new antisera against MUC3 mucin and quantitating circulating levels of MUC3 to determine if this mucin has potential as a diagnostic marker, and 3) extending their ongoing clinical evaluations of the anti-tumor activity of Nd2 immunoconjugates. It is hoped that these studies will facilitate the development of novel approaches to both the early diagnosis and treatment of pancreatic cancer.
| Nogami, H; Ohmori, H; Li, J D et al. (1997) Sp1 protein contributes to airway-specific rat MUC 2 mucin gene transcription. Gene 198:191-201 |
