Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma

Galia Tiram, Shiran Ferber, Paula Ofek, Anat Eldar-Boock, Dikla Ben-Shushan, Eilam Yeini, Adva Krivitsky, Roni Blatt, Nava Almog, Jack Henkin, Orit Amsalem, Eylon Yavin, Gadi Cohen, Philip Lazarovici, Joo Sang Lee, Eytan Ruppin, Michael Milyavsky, Rachel Grossman, Zvi Ram, Marcelo CalderónRainer Haag, Ronit Satchi-Fainaro*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Glioblastoma is an aggressive and invasive brain malignancy with high mortality ratesdespite current treatment modalities. In this study, we show that a 7-gene signature, previously found to govern the switch of glioblastomas from dormancy to aggressive tumor growth, correlates with improved overall survival of patients with glioblastoma. Using glioblastoma dormancy models, we validated the role of 2 genes from the signature, thrombospondin-1 (TSP-1) and epidermal growth factor receptor (EGFR), as regulators of glioblastoma dormancy and explored their therapeutic potential. EGFRup-regulationwas reversed using EGFR small interfering RNA polyplex, antibody, orsmall-molecule inhibitor. The diminished function of TSP-1 was augmented via a peptidomimetic. The combination of EGFR inhibition and TSP-1 restoration led to enhanced therapeutic efficacy in vitro, in3-dimensional patient-derived spheroids,and ina subcutaneous human glioblastoma model in vivo. Systemic administration of the combination therapy to mice bearing intracranial murine glioblastoma resulted inmarginal therapeutic outcomes, probably due to brain delivery challenges, p53 mutation status, and the aggressive nature of the selected cell line.Nevertheless, this study provides a proof of concept for exploiting regulators of tumor dormancy for glioblastomatherapy. This therapeutic strategy can be exploited for future investigations using a variety of therapeutic entities thatmanipulate the expression of dormancy-associated genes in glioblastoma as well as in other cancer types.

Original languageEnglish (US)
Pages (from-to)5835-5850
Number of pages16
JournalFASEB Journal
Volume32
Issue number11
DOIs
StatePublished - Nov 2018

Keywords

  • Angiogenic switch
  • EGFR inhibitiors
  • Nanomedicine
  • Polyglycerolamine
  • TSP-1 peptidomimetic

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Tiram, G., Ferber, S., Ofek, P., Eldar-Boock, A., Ben-Shushan, D., Yeini, E., Krivitsky, A., Blatt, R., Almog, N., Henkin, J., Amsalem, O., Yavin, E., Cohen, G., Lazarovici, P., Lee, J. S., Ruppin, E., Milyavsky, M., Grossman, R., Ram, Z., ... Satchi-Fainaro, R. (2018). Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma. FASEB Journal, 32(11), 5835-5850. https://doi.org/10.1096/fj.201701568R