Poster Presentation 25th Lorne Cancer Conference 2013

Exploiting the receptor uPARAP/Endo180 for targeted delivery of anti-cancer drugs to sarcomas and glioblastomas (#296)

Christoffer Nielsen 1 , Kristine R. Sørensen 1 , Kara L. Perrow 2 , Vineesh I. Chandran 2 , Lars H. Engelholm 1 , Marie Ranson 2 , Niels Behrendt 1
  1. Finsen Laboratory / BRIC, Copenhagen University Hospital, Copenhagen, Denmark
  2. School of Biological Sciences, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia

Our laboratories have identified a receptor, urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180) which is expressed in several cancers [1-3]. Notably, uPARAP/Endo180-positive cancer cells include sarcomas and glioblastomas [4] (and our unpublished results). This receptor is responsible for collagen turnover during malignant cancer invasion. By conjugating potent anti-mitotic, synthetic N-alkylated isatin derivatives [5] to antibodies targeting this receptor forming immunoconjugates, we have recently shown that uPARAP/Endo180 can be utilized to deliver the toxin specifically to uPARAP/Endo180-positive cells in vitro. Using this strategy, we have found conditions where almost 100% of cells treated with an uPARAP/Endo180-targeted isatin-immunoconjugate were killed, while cells treated with non-targeted isatin-immunoconjugate were left fully viable. Our findings point to uPARAP/Endo180 as a potential target for anti-cancer therapy, and isatin derivatives as potential cytotoxic anti-cancer drugs in connection with targeted drug delivery. Current studies are focused on the development and optimization of several different approaches for the synthesis of isatin-immunoconjugates, delivery of other drugs including doxorubicin and small interfering (si)RNA, as well as investigating the structural and cellular requirements for successful drug delivery using these immunoconjugate systems. These studies may lead to the development of novel forms of targeted therapy against sarcomas and glioblastomas, for which there is a strong need for improved treatment.

  1. Engelholm, L.H., et al., The collagen receptor uPARAP/Endo180. Front Biosci, 2009. 14: p. 2103-14.
  2. Behrendt, N., et al., A urokinase receptor-associated protein with specific collagen binding properties. J Biol Chem, 2000. 275(3): p. 1993-2002.
  3. Engelholm, L.H., et al., uPARAP/Endo180 is essential for cellular uptake of collagen and promotes fibroblast collagen adhesion. J Cell Biol, 2003. 160(7): p. 1009-15.
  4. Huijbers, I.J., et al., A role for fibrillar collagen deposition and the collagen internalization receptor endo180 in glioma invasion. PLoS One, 2010. 5(3): p. e9808.
  5. Vine, K.L., et al., In vitro cytotoxicity evaluation of some substituted isatin derivatives. Bioorg Med Chem, 2007. 15(2): p. 931-8.