Abstract 2868: Pancreatic tumor stromal cells express high levels of α-glutamyl transferase that may be employed to deliver a metabolism inhibitor to the tumor mass

Abstract

Abstract Tumors of the pancreas have the most prominent stromal/desmoplastic reaction of all epithelial tumors. This reaction is mediated by the cancer-associated stellate cells. These cells interact closely with pancreatic cancer cells to promote cancer cell survival, local tumor growth and distant metastasis (1). We have found that cancer-associated human pancreatic stellate cells express up to 30-fold higher levels of α-glutamyl transferase (≥GT) on their surface than normal pancreatic stellate cells. βGT catalyzes the transfer of the α-glutamyl moiety of glutathione to an acceptor that may be an amino acid, a peptide or water (forming glutamate). This observation suggests that this enzyme could be used to deliver a αGT-activated prodrug to the tumor mass. We have tested this theory using the glutathionylated arsenical, GSAO. GSAO is converted to GCAO by cell surface αGT, which then crosses the plasma membrane and inactivates the mitochondrial inner-membrane transporter, adenine nucleotide translocase (2). The mitochondrial perturbation leads to proliferation arrest and then cell death. GSAO was converted to GCAO by cancer-associated stellate cells and this metabolism was blocked by the αGT inhibitor, ABBA. The activated GSAO inhibited proliferation of both tumor and endothelial cells by 43 to 100% and 41 to 75%, respectively. We also observed a positive correlation (R2=0.883) between the αGT activity of pancreatic tumor cells and proliferation arrest of co-cultured endothelial cells by GSAO. We have established an orthotopic model of human pancreatic cancer in mice where tumor cells are implanted without or with cancer-associated stellate cells. The anti-tumor efficacy of systemically administered GSAO is currently being evaluated in this model. These observations suggest that the high expression of αGT on pancreatic tumor stromal cells may be employed to deliver a αGT-activated prodrug to the tumor mass. 1. Vonlaufen, A., Phillips, P. A., Xu, Z., Goldstein, D., Pirola, R. C., Wilson, J. S., and Apte, M. V. (2008) Cancer Res. 68, 7707-7710 2. Dilda, P. J., Ramsay, E. E., Corti, A., Pompella, A., and Hogg, P. J. (2008) J. Biol. Chem. 283, 35428-35434 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2868. doi:1538-7445.AM2012-2868