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

  1. Shiran Ferber
  2. Galia Tiram
  3. Ana Sousa-Herves
  4. Anat Eldar-Boock
  5. Adva Krivitsky
  6. Anna Scomparin
  7. Eilam Yeini
  8. Paula Ofek
  9. Dikla Ben-Shushan
  10. Laura Isabel Vossen
  11. Kai Licha
  12. Rachel Grossman
  13. Zvi Ram
  14. Jack Henkin
  15. Eytan Ruppin
  16. Noam Auslander
  17. Rainer Haag
  18. Marcelo Calderón
  19. Ronit Satchi-Fainaro  Is a corresponding author
  1. Tel Aviv University, Israel
  2. Freie Universität Berlin, Germany
  3. Tel Aviv Sourasky Medical Center, Israel
  4. Northwestern University, United States
  5. University of Maryland, United States

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.

Article and author information

Author details

  1. Shiran Ferber

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Galia Tiram

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Ana Sousa-Herves

    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Anat Eldar-Boock

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Adva Krivitsky

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Anna Scomparin

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Eilam Yeini

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Paula Ofek

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Dikla Ben-Shushan

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Laura Isabel Vossen

    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Kai Licha

    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Rachel Grossman

    Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  13. Zvi Ram

    Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  14. Jack Henkin

    Chemistry of Life Processes Institute, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Eytan Ruppin

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  16. Noam Auslander

    Department of Computer science, University of Maryland, College Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Rainer Haag

    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  18. Marcelo Calderón

    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  19. Ronit Satchi-Fainaro

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    For correspondence
    ronitsf@post.tau.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7360-7837

Funding

H2020 European Research Council (617445)

  • Ronit Satchi-Fainaro

Israel Science Foundation (918/14)

  • Ronit Satchi-Fainaro

Israel Cancer Association (20150909)

  • Ronit Satchi-Fainaro

Bundesministerium für Bildung und Forschung (13N11536)

  • Rainer Haag

Bundesministerium für Bildung und Forschung (13N12561)

  • Marcelo Calderón

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animals were housed in the Tel Aviv University animal facility. The experiments were approved by the animal care and use committee (IACUC) of Tel Aviv University (approval no. 01-12-064, 01-12-065) and conducted in accordance with NIH guidelines.

Human subjects: Experiments involving human tissues were performed with the approval of the Institutional Review Board (IRB) and in compliance with all legal and ethical considerations for human subject research (approval no. 0735-13-TLV). Single human plasma was obtained from a healthy consented unmedicated donor according to German ethical guidelines.

Reviewing Editor

  1. Charles L Sawyers, Memorial Sloan-Kettering Cancer Center, United States

Publication history

  1. Received: January 23, 2017
  2. Accepted: October 3, 2017
  3. Accepted Manuscript published: October 4, 2017 (version 1)
  4. Version of Record published: October 17, 2017 (version 2)
  5. Version of Record updated: November 3, 2017 (version 3)

Copyright

© 2017, Ferber et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,597
    Page views
  • 528
    Downloads
  • 42
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Shiran Ferber
  2. Galia Tiram
  3. Ana Sousa-Herves
  4. Anat Eldar-Boock
  5. Adva Krivitsky
  6. Anna Scomparin
  7. Eilam Yeini
  8. Paula Ofek
  9. Dikla Ben-Shushan
  10. Laura Isabel Vossen
  11. Kai Licha
  12. Rachel Grossman
  13. Zvi Ram
  14. Jack Henkin
  15. Eytan Ruppin
  16. Noam Auslander
  17. Rainer Haag
  18. Marcelo Calderón
  19. Ronit Satchi-Fainaro
(2017)
Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome
eLife 6:e25281.
https://doi.org/10.7554/eLife.25281

Further reading

    1. Cancer Biology
    2. Computational and Systems Biology
    Xiangkun Wu, Hong Yan ... Li Liang
    Research Article

    Colorectal cancer (CRC) remains a challenging and deadly disease with high tumor microenvironment (TME) heterogeneity. Using an integrative multi-omics analysis and artificial intelligence-enabled spatial analysis of whole-slide images, we performed a comprehensive characterization of TME in colorectal cancer (CCCRC). CRC samples were classified into four CCCRC subtypes with distinct TME features, namely, C1 as the proliferative subtype with low immunogenicity; C2 as the immunosuppressed subtype with the terminally exhausted immune characteristics; C3 as the immune-excluded subtype with the distinct upregulation of stromal components and a lack of T cell infiltration in the tumor core; and C4 as the immunomodulatory subtype with the remarkable upregulation of anti-tumor immune components. The four CCCRC subtypes had distinct histopathologic and molecular characteristics, therapeutic efficacy, and prognosis. We found that the C1 subtype may be suitable for chemotherapy and cetuximab, the C2 subtype may benefit from a combination of chemotherapy and bevacizumab, the C3 subtype has increased sensitivity to the WNT pathway inhibitor WIKI4, and the C4 subtype is a potential candidate for immune checkpoint blockade treatment. Importantly, we established a simple gene classifier for accurate identification of each CCCRC subtype. Collectively our integrative analysis ultimately established a holistic framework to thoroughly dissect the TME of CRC, and the CCCRC classification system with high biological interpretability may contribute to biomarker discovery and future clinical trial design.

    1. Cancer Biology
    Jiangfei Chen, Kunal Baxi ... Myron S Ignatius
    Research Article

    In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53P153D and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153D unexpectedly also predisposes to hedgehog expressing medulloblastomas in the kRASG12D-driven ERMS-model.