Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome

Shiran Ferber; Galia Tiram; Ana Sousa-Herves; Anat Eldar-Boock; Adva Krivitsky; Anna Scomparin; Eilam Yeini; Paula Ofek; Dikla Ben-Shushan; Laura Isabel Vossen; Kai Licha; Rachel Grossman; Zvi Ram; Jack Henkin; Eytan Ruppin; Noam Auslander; Rainer Haag; Marcelo Calderón; Ronit Satchi-Fainaro

doi:10.7554/eLife.25281

Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome

Shiran Ferber, Galia Tiram, Ana Sousa-Herves, Anat Eldar-Boock, Adva Krivitsky, Anna Scomparin, Eilam Yeini, Paula Ofek, Dikla Ben-Shushan, Laura Isabel Vossen, Kai Licha, Rachel Grossman, Zvi Ram, Jack Henkin, Eytan Ruppin, Noam Auslander, Rainer Haag, Marcelo Calderón, Ronit Satchi-Fainaro^*

^*Corresponding author for this work

CLP - Chemistry of Life Processes Institute

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

58 Scopus citations

Abstract

Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB, bind to P/L-selectins and accumulate selectively in intracranial tumors. We show that dPGS has dual targeting properties, as we found that P-selectin is not only expressed on tumor endothelium but also on glioblastoma cells. We delivered dPGS-PTX in combination with a peptidomimetic of the anti-angiogenic protein thrombospondin-1 (TSP-1 PM). This combination resulted in a remarkable synergistic anticancer effect on intracranial human and murine glioblastoma via induction of Fas and Fas-L, with no side effects compared to free PTX or temozolomide. This study shows that our unique therapeutic approach offers a viable alternative for the treatment of glioblastoma.

Original language	English (US)
Article number	e25281
Journal	eLife
Volume	6
DOIs	https://doi.org/10.7554/eLife.25281
State	Published - Oct 4 2017

Funding

RS-F and RH would like to thank the German-Israel Foundation (GIF) for financial support. RS-F, MC and RH thank Tel Aviv University and Freie Universität Berlin for financial support to organize collaborative workshops. The Satchi-Fainaro laboratory’s research leading to these results has received partial funding from the European Research Council under the European Union’s Seventh Frame-work Programme (FP/2007–2013)/ERC Consolidator Grant Agreement n. [617445], from the Israel Science Foundation (918/14), from Nancy and Peter Brown friends of the Israel Cancer Association ICA USA, in Memory of Kenny and Michael Adler, and from the Morris Kahn Foundation. RH acknowledges financial support from the Bundesmiminsterium für Bildung und Forschung (BMBF) within the Biotransporter project (project number: 13N11536) and the SFB 765. MC gratefully acknowledges financial support from the BMBF through the NanoMatFutur award (13N12561) and the focus area Nanoscale of the Freie Universität Berlin (http://www.nanoscale.fu-berlin.de). ASH is grateful for a Marie Curie Intra-European Fellowship (302717). We thank Prof. Adit Ben-Baruch and Yulia Liubomirski for their professional assistance with the tumor spheroids model. We thank Lior Bikovski for his assistance with the behavioral studies performed at the Myers neuro-behavioral core facility at the Sackler Faculty of Medicine, Tel Aviv University. RS-F and RH would like to thank the German-Israel Foundation (GIF) for financial support. RS-F, MC and RH thank Tel Aviv University and Freie Universität Berlin for financial support to organize collab-orative workshops. The Satchi-Fainaro laboratory’s research leading to these results has received partial funding from the European Research Council under the European Union’s Seventh Frame-work Programme (FP/2007-2013)/ERC Consolidator Grant Agreement n. [617445], from the Israel Science Foundation (918/14), from Nancy and Peter Brown friends of the Israel Cancer Association ICA USA, in Memory of Kenny and Michael Adler, and from the Morris Kahn Foundation. RH acknowledges financial support from the Bundesmiminsterium für Bildung und Forschung (BMBF) within the Biotransporter project (project number: 13N11536) and the SFB 765. MC gratefully acknowledges financial support from the BMBF through the NanoMatFutur award (13N12561) and the focus area Nanoscale of the Freie Universität Berlin (http://www.nanoscale.fu-berlin.de). ASH is grateful for a Marie Curie Intra-European Fellowship (302717). We thank Prof. Adit Ben-Baruch and Yulia Liubomirski for their professional assistance with the tumor spheroids model. We thank Lior Bikovski for his assistance with the behavioral studies performed at the Myers neuro-behavioral core facility at the Sackler Faculty of Medicine, Tel Aviv University.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology
General Neuroscience

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10.7554/eLife.25281

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Ferber, S., Tiram, G., Sousa-Herves, A., Eldar-Boock, A., Krivitsky, A., Scomparin, A., Yeini, E., Ofek, P., Ben-Shushan, D., Vossen, L. I., Licha, K., Grossman, R., Ram, Z., Henkin, J., Ruppin, E., Auslander, N., Haag, R., Calderón, M., & Satchi-Fainaro, R. (2017). Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome. eLife, 6, Article e25281. https://doi.org/10.7554/eLife.25281

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title = "Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome",

abstract = "Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB, bind to P/L-selectins and accumulate selectively in intracranial tumors. We show that dPGS has dual targeting properties, as we found that P-selectin is not only expressed on tumor endothelium but also on glioblastoma cells. We delivered dPGS-PTX in combination with a peptidomimetic of the anti-angiogenic protein thrombospondin-1 (TSP-1 PM). This combination resulted in a remarkable synergistic anticancer effect on intracranial human and murine glioblastoma via induction of Fas and Fas-L, with no side effects compared to free PTX or temozolomide. This study shows that our unique therapeutic approach offers a viable alternative for the treatment of glioblastoma.",

author = "Shiran Ferber and Galia Tiram and Ana Sousa-Herves and Anat Eldar-Boock and Adva Krivitsky and Anna Scomparin and Eilam Yeini and Paula Ofek and Dikla Ben-Shushan and Vossen, {Laura Isabel} and Kai Licha and Rachel Grossman and Zvi Ram and Jack Henkin and Eytan Ruppin and Noam Auslander and Rainer Haag and Marcelo Calder{\'o}n and Ronit Satchi-Fainaro",

note = "Funding Information: RS-F and RH would like to thank the German-Israel Foundation (GIF) for financial support. RS-F, MC and RH thank Tel Aviv University and Freie Universit{\"a}t Berlin for financial support to organize collaborative workshops. The Satchi-Fainaro laboratory{\textquoteright}s research leading to these results has received partial funding from the European Research Council under the European Union{\textquoteright}s Seventh Frame-work Programme (FP/2007–2013)/ERC Consolidator Grant Agreement n. [617445], from the Israel Science Foundation (918/14), from Nancy and Peter Brown friends of the Israel Cancer Association ICA USA, in Memory of Kenny and Michael Adler, and from the Morris Kahn Foundation. RH acknowledges financial support from the Bundesmiminsterium f{\"u}r Bildung und Forschung (BMBF) within the Biotransporter project (project number: 13N11536) and the SFB 765. MC gratefully acknowledges financial support from the BMBF through the NanoMatFutur award (13N12561) and the focus area Nanoscale of the Freie Universit{\"a}t Berlin (http://www.nanoscale.fu-berlin.de). ASH is grateful for a Marie Curie Intra-European Fellowship (302717). We thank Prof. Adit Ben-Baruch and Yulia Liubomirski for their professional assistance with the tumor spheroids model. We thank Lior Bikovski for his assistance with the behavioral studies performed at the Myers neuro-behavioral core facility at the Sackler Faculty of Medicine, Tel Aviv University. Funding Information: RS-F and RH would like to thank the German-Israel Foundation (GIF) for financial support. RS-F, MC and RH thank Tel Aviv University and Freie Universit{\"a}t Berlin for financial support to organize collab-orative workshops. The Satchi-Fainaro laboratory{\textquoteright}s research leading to these results has received partial funding from the European Research Council under the European Union{\textquoteright}s Seventh Frame-work Programme (FP/2007-2013)/ERC Consolidator Grant Agreement n. [617445], from the Israel Science Foundation (918/14), from Nancy and Peter Brown friends of the Israel Cancer Association ICA USA, in Memory of Kenny and Michael Adler, and from the Morris Kahn Foundation. RH acknowledges financial support from the Bundesmiminsterium f{\"u}r Bildung und Forschung (BMBF) within the Biotransporter project (project number: 13N11536) and the SFB 765. MC gratefully acknowledges financial support from the BMBF through the NanoMatFutur award (13N12561) and the focus area Nanoscale of the Freie Universit{\"a}t Berlin (http://www.nanoscale.fu-berlin.de). ASH is grateful for a Marie Curie Intra-European Fellowship (302717). We thank Prof. Adit Ben-Baruch and Yulia Liubomirski for their professional assistance with the tumor spheroids model. We thank Lior Bikovski for his assistance with the behavioral studies performed at the Myers neuro-behavioral core facility at the Sackler Faculty of Medicine, Tel Aviv University. Publisher Copyright: {\textcopyright} Ferber et al.",

year = "2017",

month = oct,

day = "4",

doi = "10.7554/eLife.25281",

language = "English (US)",

volume = "6",

journal = "eLife",

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Ferber, S, Tiram, G, Sousa-Herves, A, Eldar-Boock, A, Krivitsky, A, Scomparin, A, Yeini, E, Ofek, P, Ben-Shushan, D, Vossen, LI, Licha, K, Grossman, R, Ram, Z, Henkin, J, Ruppin, E, Auslander, N, Haag, R, Calderón, M & Satchi-Fainaro, R 2017, 'Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome', eLife, vol. 6, e25281. https://doi.org/10.7554/eLife.25281

TY - JOUR

T1 - Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome

AU - Ferber, Shiran

AU - Tiram, Galia

AU - Sousa-Herves, Ana

AU - Eldar-Boock, Anat

AU - Krivitsky, Adva

AU - Scomparin, Anna

AU - Yeini, Eilam

AU - Ofek, Paula

AU - Ben-Shushan, Dikla

AU - Vossen, Laura Isabel

AU - Licha, Kai

AU - Grossman, Rachel

AU - Ram, Zvi

AU - Henkin, Jack

AU - Ruppin, Eytan

AU - Auslander, Noam

AU - Haag, Rainer

AU - Calderón, Marcelo

AU - Satchi-Fainaro, Ronit

N1 - Funding Information: RS-F and RH would like to thank the German-Israel Foundation (GIF) for financial support. RS-F, MC and RH thank Tel Aviv University and Freie Universität Berlin for financial support to organize collaborative workshops. The Satchi-Fainaro laboratory’s research leading to these results has received partial funding from the European Research Council under the European Union’s Seventh Frame-work Programme (FP/2007–2013)/ERC Consolidator Grant Agreement n. [617445], from the Israel Science Foundation (918/14), from Nancy and Peter Brown friends of the Israel Cancer Association ICA USA, in Memory of Kenny and Michael Adler, and from the Morris Kahn Foundation. RH acknowledges financial support from the Bundesmiminsterium für Bildung und Forschung (BMBF) within the Biotransporter project (project number: 13N11536) and the SFB 765. MC gratefully acknowledges financial support from the BMBF through the NanoMatFutur award (13N12561) and the focus area Nanoscale of the Freie Universität Berlin (http://www.nanoscale.fu-berlin.de). ASH is grateful for a Marie Curie Intra-European Fellowship (302717). We thank Prof. Adit Ben-Baruch and Yulia Liubomirski for their professional assistance with the tumor spheroids model. We thank Lior Bikovski for his assistance with the behavioral studies performed at the Myers neuro-behavioral core facility at the Sackler Faculty of Medicine, Tel Aviv University. Funding Information: RS-F and RH would like to thank the German-Israel Foundation (GIF) for financial support. RS-F, MC and RH thank Tel Aviv University and Freie Universität Berlin for financial support to organize collab-orative workshops. The Satchi-Fainaro laboratory’s research leading to these results has received partial funding from the European Research Council under the European Union’s Seventh Frame-work Programme (FP/2007-2013)/ERC Consolidator Grant Agreement n. [617445], from the Israel Science Foundation (918/14), from Nancy and Peter Brown friends of the Israel Cancer Association ICA USA, in Memory of Kenny and Michael Adler, and from the Morris Kahn Foundation. RH acknowledges financial support from the Bundesmiminsterium für Bildung und Forschung (BMBF) within the Biotransporter project (project number: 13N11536) and the SFB 765. MC gratefully acknowledges financial support from the BMBF through the NanoMatFutur award (13N12561) and the focus area Nanoscale of the Freie Universität Berlin (http://www.nanoscale.fu-berlin.de). ASH is grateful for a Marie Curie Intra-European Fellowship (302717). We thank Prof. Adit Ben-Baruch and Yulia Liubomirski for their professional assistance with the tumor spheroids model. We thank Lior Bikovski for his assistance with the behavioral studies performed at the Myers neuro-behavioral core facility at the Sackler Faculty of Medicine, Tel Aviv University. Publisher Copyright: © Ferber et al.

PY - 2017/10/4

Y1 - 2017/10/4

N2 - Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB, bind to P/L-selectins and accumulate selectively in intracranial tumors. We show that dPGS has dual targeting properties, as we found that P-selectin is not only expressed on tumor endothelium but also on glioblastoma cells. We delivered dPGS-PTX in combination with a peptidomimetic of the anti-angiogenic protein thrombospondin-1 (TSP-1 PM). This combination resulted in a remarkable synergistic anticancer effect on intracranial human and murine glioblastoma via induction of Fas and Fas-L, with no side effects compared to free PTX or temozolomide. This study shows that our unique therapeutic approach offers a viable alternative for the treatment of glioblastoma.

AB - Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB, bind to P/L-selectins and accumulate selectively in intracranial tumors. We show that dPGS has dual targeting properties, as we found that P-selectin is not only expressed on tumor endothelium but also on glioblastoma cells. We delivered dPGS-PTX in combination with a peptidomimetic of the anti-angiogenic protein thrombospondin-1 (TSP-1 PM). This combination resulted in a remarkable synergistic anticancer effect on intracranial human and murine glioblastoma via induction of Fas and Fas-L, with no side effects compared to free PTX or temozolomide. This study shows that our unique therapeutic approach offers a viable alternative for the treatment of glioblastoma.

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U2 - 10.7554/eLife.25281

DO - 10.7554/eLife.25281

M3 - Article

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AN - SCOPUS:85036508928

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VL - 6

JO - eLife

JF - eLife

M1 - e25281

ER -

Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome

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