Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

• DOI: 10.1016/j.ccell.2015.09.003
• Publication Date: 2015-10-13T00:57:24Z
• Authors: Ali Salanti; Thomas M. Clausen; Mette Ø. Agerbæk; Nader Al Nakouzi; Madeleine Dahlbäck; Htoo Z. Oo; Sherry Lee; Tobias Gustavsson; Jamie R. Rich; Bradley J. Hedberg; Yang Mao; Line Barington; Marina A. Pereira; Janine LoBello; Makoto Endo; Ladan Fazli; Jo Soden; Chris K. Wang; Adam F. Sander; Robert Dagil; Susan Thrane; Peter J. Holst; Le Meng; Francesco Favero; Glen J. Weiss; Morten A. Nielsen; Jim Freeth; Torsten O. Nielsen; Joseph Zaia; Nhan L. Tran; Jeff Trent; John S. Babcook; Thor G. Theander; Poul H. Sorensen; Mads Daugaard
• Keywords: 0301 basic medicine; Cancer Research; Skin Neoplasms; Placenta; Melanoma, Experimental; Antigens, Protozoan; Mice; 03 medical and health sciences; Pregnancy; Cell Line, Tumor; Human Umbilical Vein Endothelial Cells; Animals; Humans; Molecular Targeted Therapy; 0303 health sciences; Chondroitin Sulfates; Membrane Proteins; Cell Biology; Recombinant Proteins; 3. Good health; HEK293 Cells; Hyaluronan Receptors; Oncology; Chondroitin Sulfate Proteoglycans; Organ Specificity; Female; Oligopeptides

Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification.