Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Ali Salanti; Thomas M Clausen; Mette Ø Agerbæk; Nader Al Nakouzi; Madeleine Dahlbäck; Htoo Zarni 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

doi:10.1016/j.ccell.2015.09.003

Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Cancer Cell. 2015 Oct 12;28(4):500-514. doi: 10.1016/j.ccell.2015.09.003.

Authors

Ali Salanti¹, Thomas M Clausen², Mette Ø Agerbæk³, Nader Al Nakouzi⁴, Madeleine Dahlbäck⁵, Htoo Zarni Oo⁴, Sherry Lee⁶, Tobias Gustavsson⁵, Jamie R Rich⁷, Bradley J Hedberg⁷, Yang Mao⁸, Line Barington⁵, Marina A Pereira⁵, Janine LoBello⁹, Makoto Endo¹⁰, Ladan Fazli⁶, Jo Soden¹¹, Chris K Wang⁶, Adam F Sander⁵, Robert Dagil⁵, Susan Thrane⁵, Peter J Holst⁵, Le Meng⁸, Francesco Favero¹², Glen J Weiss¹³, Morten A Nielsen⁵, Jim Freeth¹¹, Torsten O Nielsen¹⁴, Joseph Zaia⁸, Nhan L Tran⁹, Jeff Trent⁹, John S Babcook⁷, Thor G Theander⁵, Poul H Sorensen¹⁵, Mads Daugaard¹⁶

Affiliations

¹ Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, 1014 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, 2100 Copenhagen, Denmark. Electronic address: [email protected].
² Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, 1014 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, 2100 Copenhagen, Denmark; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
³ Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, 1014 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, 2100 Copenhagen, Denmark; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
⁴ Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
⁵ Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, 1014 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
⁶ Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
⁷ Kairos Therapeutics, Inc., Vancouver, BC V6T 1Z3, Canada; Centre for Drug Research and Development, Vancouver, BC V6T 1Z3, Canada.
⁸ Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
⁹ Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
¹⁰ Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Department of Anatomic Pathology, Kyushu University, Fukuoka 812-8582, Japan; Department of Orthopaedic Surgery, Kyushu University, Fukuoka 819-0395, Japan.
¹¹ Retrogenix Ltd., Crown House, Bingswood Estate, Whaley Bridge, High Peak SK23 7LY, UK.
¹² Centre for Biological Sequence Analysis, Technical University of Denmark, Lyngby 2800, Denmark.
¹³ Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA; Cancer Treatment Centers of America, Goodyear, AZ 85338, USA.
¹⁴ Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
¹⁵ Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
¹⁶ Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada. Electronic address: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antigens, Protozoan / genetics*
Antigens, Protozoan / metabolism
Cell Line, Tumor
Chondroitin Sulfate Proteoglycans / metabolism
Chondroitin Sulfates / metabolism*
Female
HEK293 Cells
Human Umbilical Vein Endothelial Cells
Humans
Hyaluronan Receptors / metabolism
Melanoma, Experimental / metabolism
Melanoma, Experimental / therapy*
Membrane Proteins / metabolism
Mice
Molecular Targeted Therapy
Oligopeptides / genetics
Oligopeptides / metabolism
Organ Specificity
Placenta / metabolism*
Pregnancy
Recombinant Proteins / administration & dosage*
Recombinant Proteins / pharmacology
Skin Neoplasms / metabolism
Skin Neoplasms / therapy*

Substances

Antigens, Protozoan
CD44 protein, human
CSPG4 protein, human
Chondroitin Sulfate Proteoglycans
Hyaluronan Receptors
Membrane Proteins
Oligopeptides
Recombinant Proteins
VAR2CSA protein, Plasmodium falciparum
hemiasterlin
Chondroitin Sulfates

Abstract

Publication types

MeSH terms

Substances

Grants and funding