@article{d967bb702dcc45cba9e940f3d4595a31,
title = "Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein",
abstract = "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.",
author = "Ali Salanti and Clausen, {Thomas M.} and Agerb{\ae}k, {Mette O.} and {Al Nakouzi}, Nader and Madeleine Dahlb{\"a}ck and Oo, {Htoo Z.} and Sherry Lee and Tobias Gustavsson and Rich, {Jamie R.} and Hedberg, {Bradley J.} and Yang Mao and Line Barington and Pereira, {Marina A.} and Janine LoBello and Makoto Endo and Ladan Fazli and Jo Soden and Wang, {Chris K.} and Sander, {Adam F.} and Robert Dagil and Susan Thrane and Holst, {Peter J.} and Le Meng and Francesco Favero and Weiss, {Glen J.} and Nielsen, {Morten A.} and Jim Freeth and Nielsen, {Torsten O.} and Joseph Zaia and Tran, {Nhan L.} and Jeff Trent and Babcook, {John S.} and Theander, {Thor G.} and Sorensen, {Poul H.} and Mads Daugaard",
note = "Funding Information: Since rVAR2 is efficiently internalized into pl-CS expressing cells, rVAR2 could potentially facilitate the delivery of anti-cancer compounds directly into the tumor environment. This notion was supported by our in vivo and ex vivo imaging experiments. We subsequently demonstrated the therapeutic potential of targeting pl-CS on human tumors by two different approaches. First, rVAR2 genetically fused to a part of the diphtheria toxin (rVAR2-DT), efficiently killed tumor cells in vitro and in vivo in a CS-dependent manner. Second, chemical conjugation of a hemiasterlin toxin to rVAR2 created a highly potent VDC886 that specifically targeted pl-CS on diverse tumor cells in vitro and in vivo. Notably, non-pregnant mice injected with rVAR2-DT or VDC886 showed no adverse treatment effects, suggesting that pl-CS is expressed below rVAR2–based detection levels in non-malignant tissue in mammals. This is supported by the observation that P. falciparum-infected erythrocytes cannot bind anywhere in vascularized tissue compartments, except in the placenta. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = oct,
day = "12",
doi = "10.1016/j.ccell.2015.09.003",
language = "English",
volume = "28",
pages = "500--514",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}
