Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Ali Salanti; Thomas M. Clausen; Mette O. 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

doi:10.1016/j.ccell.2015.09.003

Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Ali Salanti, Thomas M. Clausen, Mette O. 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 DagilSusan 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

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

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.

Original language	English (US)
Article number	2143
Pages (from-to)	500-514
Number of pages	15
Journal	Cancer cell
Volume	28
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2015.09.003
State	Published - Oct 12 2015

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Salanti, A., Clausen, T. M., Agerbæk, M. O., Al Nakouzi, N., Dahlbäck, M., Oo, H. Z., Lee, S., Gustavsson, T., Rich, J. R., Hedberg, B. J., Mao, Y., Barington, L., Pereira, M. A., LoBello, J., Endo, M., Fazli, L., Soden, J., Wang, C. K., Sander, A. F., ... Daugaard, M. (2015). Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. Cancer cell, 28(4), 500-514. [2143]. https://doi.org/10.1016/j.ccell.2015.09.003

Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. / Salanti, Ali; Clausen, Thomas M.; Agerbæk, Mette O.; Al Nakouzi, Nader; Dahlbäck, Madeleine; Oo, Htoo Z.; Lee, Sherry; Gustavsson, Tobias; Rich, Jamie R.; Hedberg, Bradley J.; Mao, Yang; Barington, Line; Pereira, Marina A.; LoBello, Janine; Endo, Makoto; Fazli, Ladan; Soden, Jo; Wang, Chris K.; Sander, Adam F.; Dagil, Robert; Thrane, Susan; Holst, Peter J.; Meng, Le; Favero, Francesco; Weiss, Glen J.; Nielsen, Morten A.; Freeth, Jim; Nielsen, Torsten O.; Zaia, Joseph; Tran, Nhan L.; Trent, Jeff; Babcook, John S.; Theander, Thor G.; Sorensen, Poul H.; Daugaard, Mads.

In: Cancer cell, Vol. 28, No. 4, 2143, 12.10.2015, p. 500-514.

Research output: Contribution to journal › Article › peer-review

Salanti, A, Clausen, TM, Agerbæk, MO, Al Nakouzi, N, Dahlbäck, M, Oo, HZ, Lee, S, Gustavsson, T, Rich, JR, Hedberg, BJ, Mao, Y, Barington, L, Pereira, MA, LoBello, J, Endo, M, Fazli, L, Soden, J, Wang, CK, Sander, AF, Dagil, R, Thrane, S, Holst, PJ, Meng, L, Favero, F, Weiss, GJ, Nielsen, MA, Freeth, J, Nielsen, TO, Zaia, J, Tran, NL, Trent, J, Babcook, JS, Theander, TG, Sorensen, PH & Daugaard, M 2015, 'Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein', Cancer cell, vol. 28, no. 4, 2143, pp. 500-514. https://doi.org/10.1016/j.ccell.2015.09.003

Salanti, Ali ; Clausen, Thomas M. ; Agerbæk, Mette O. ; Al Nakouzi, Nader ; Dahlbäck, Madeleine ; Oo, Htoo Z. ; Lee, Sherry ; Gustavsson, Tobias ; Rich, Jamie R. ; Hedberg, Bradley J. ; Mao, Yang ; Barington, Line ; Pereira, Marina A. ; LoBello, Janine ; Endo, Makoto ; Fazli, Ladan ; Soden, Jo ; Wang, Chris K. ; Sander, Adam F. ; Dagil, Robert ; Thrane, Susan ; Holst, Peter J. ; Meng, Le ; Favero, Francesco ; Weiss, Glen J. ; Nielsen, Morten A. ; Freeth, Jim ; Nielsen, Torsten O. ; Zaia, Joseph ; Tran, Nhan L. ; Trent, Jeff ; Babcook, John S. ; Theander, Thor G. ; Sorensen, Poul H. ; Daugaard, Mads. / Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. In: Cancer cell. 2015 ; Vol. 28, No. 4. pp. 500-514.

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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: The work was supported by funds from the Novo Nordisk Foundation; the Danish Cancer Society; and Stand Up To Cancer – St. Baldrick{\textquoteright}s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research; Augustinus Foundation; U.S. Department of Defense (DoD); the Harboe Foundation; the European Research Councils (ERC) through the MalOnco program; The Danish Innovation Foundation; VAR2 Pharmaceuticals; Kairos Therapeutics; the Spar Nord Foundation; Team Finn and other riders in the Ride to Conquer Cancer; Safeway; and the Prostate Cancer Canada (PCC) Foundation. A.S., M.D., T.G.T., and P.H.S. are shareholders of VAR2 Pharmaceuticals ApS and members of the board of directors. J.R., B.H., and J.B. are employees of Kairos Therapeutics, Inc. J.F. and J.S. are employees of Retrogenix Ltd. ",

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T1 - Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

AU - Salanti, Ali

AU - Clausen, Thomas M.

AU - Agerbæk, Mette O.

AU - Al Nakouzi, Nader

AU - Dahlbäck, Madeleine

AU - Oo, Htoo Z.

AU - Lee, Sherry

AU - Gustavsson, Tobias

AU - Rich, Jamie R.

AU - Hedberg, Bradley J.

AU - Mao, Yang

AU - Barington, Line

AU - Pereira, Marina A.

AU - LoBello, Janine

AU - Endo, Makoto

AU - Fazli, Ladan

AU - Soden, Jo

AU - Wang, Chris K.

AU - Sander, Adam F.

AU - Dagil, Robert

AU - Thrane, Susan

AU - Holst, Peter J.

AU - Meng, Le

AU - Favero, Francesco

AU - Weiss, Glen J.

AU - Nielsen, Morten A.

AU - Freeth, Jim

AU - Nielsen, Torsten O.

AU - Zaia, Joseph

AU - Tran, Nhan L.

AU - Trent, Jeff

AU - Babcook, John S.

AU - Theander, Thor G.

AU - Sorensen, Poul H.

AU - Daugaard, Mads

N1 - Funding Information: The work was supported by funds from the Novo Nordisk Foundation; the Danish Cancer Society; and Stand Up To Cancer – St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research; Augustinus Foundation; U.S. Department of Defense (DoD); the Harboe Foundation; the European Research Councils (ERC) through the MalOnco program; The Danish Innovation Foundation; VAR2 Pharmaceuticals; Kairos Therapeutics; the Spar Nord Foundation; Team Finn and other riders in the Ride to Conquer Cancer; Safeway; and the Prostate Cancer Canada (PCC) Foundation. A.S., M.D., T.G.T., and P.H.S. are shareholders of VAR2 Pharmaceuticals ApS and members of the board of directors. J.R., B.H., and J.B. are employees of Kairos Therapeutics, Inc. J.F. and J.S. are employees of Retrogenix Ltd.

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