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.
authors.affiliation: 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: salanti@sund.ku.dk.
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
authors.affiliation: 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.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Clausen
authors.affiliation: 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.
authors.forename: Mette Ø
authors.initials: MØ
authors.lastname: Agerbæk
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Nader
authors.initials: N
authors.lastname: Al Nakouzi
authors.affiliation: 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.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Dahlbäck
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Htoo Zarni
authors.initials: HZ
authors.lastname: Oo
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Sherry
authors.initials: S
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Tobias
authors.initials: T
authors.lastname: Gustavsson
authors.affiliation: Kairos Therapeutics, Inc., Vancouver, BC V6T 1Z3, Canada; Centre for Drug Research and Development, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Rich
authors.affiliation: Kairos Therapeutics, Inc., Vancouver, BC V6T 1Z3, Canada; Centre for Drug Research and Development, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Hedberg
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Mao
authors.affiliation: 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.
authors.forename: Line
authors.initials: L
authors.lastname: Barington
authors.affiliation: 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.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Pereira
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
authors.forename: Janine
authors.initials: J
authors.lastname: LoBello
authors.affiliation: 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.
authors.forename: Makoto
authors.initials: M
authors.lastname: Endo
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Retrogenix Ltd., Crown House, Bingswood Estate, Whaley Bridge, High Peak SK23 7LY, UK.
authors.forename: Jo
authors.initials: J
authors.lastname: Soden
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Chris K
authors.initials: CK
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Sander
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Dagil
authors.affiliation: 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.
authors.forename: Susan
authors.initials: S
authors.lastname: Thrane
authors.affiliation: 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.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Holst
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Meng
authors.affiliation: Centre for Biological Sequence Analysis, Technical University of Denmark, Lyngby 2800, Denmark.
authors.forename: Francesco
authors.initials: F
authors.lastname: Favero
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA; Cancer Treatment Centers of America, Goodyear, AZ 85338, USA.
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.affiliation: 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.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Nielsen
authors.affiliation: Retrogenix Ltd., Crown House, Bingswood Estate, Whaley Bridge, High Peak SK23 7LY, UK.
authors.forename: Jim
authors.initials: J
authors.lastname: Freeth
authors.affiliation: 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.
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zaia
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Trent
authors.affiliation: Kairos Therapeutics, Inc., Vancouver, BC V6T 1Z3, Canada; Centre for Drug Research and Development, Vancouver, BC V6T 1Z3, Canada.
authors.forename: John S
authors.initials: JS
authors.lastname: Babcook
authors.affiliation: 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.
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Poul H
authors.initials: PH
authors.lastname: Sorensen
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada. Electronic address: mads.daugaard@ubc.ca.
authors.forename: Mads
authors.initials: M
authors.lastname: Daugaard
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000628:therapy*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D012878:Skin Neoplasms / Q000378:metabolism / Q000628:therapy*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000953:Antigens, Protozoan; D011508:Chondroitin Sulfate Proteoglycans; D002809:Chondroitin Sulfates; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D009842:Oligopeptides; D011994:Recombinant Proteins; C497483:CD44 protein, human; C101390:CSPG4 protein, human; D000099216:Chondroitin Sulfate Proteoglycan 4; C512601:VAR2CSA protein, Plasmodium falciparum; C467070:hemiasterlin