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 journalArticlepeer-review

12 Scopus citations


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 languageAmerican English
Pages (from-to)5835-5850
Number of pages16
JournalFASEB Journal
Issue number11
StatePublished - Nov 2018

Bibliographical note

Funding Information:
The authors thank Prof. Itai Benhar (Tel Aviv University), Dr. Moshe Elkabets, and Dr. Limor Cohen (Ben-Gurion University of the Negev, Beersheba, Israel) for insightful advice on antibodies and small molecules targeting EGFR. R.S.-F and R.H. were supported by the German-Israel Foundation. R.S.-F, M.C., and R.H. thank Tel Aviv University and Freie Universität Berlin for financial support to organize collaborative workshops. The Satchi-Fainaro laboratory (Tel Aviv University) has received partial funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/European Research Council (ERC) Consolidator Grant Agreement POLYDORM 617445; the Magneton Program of the Office of the Chief Scientist of the Israel Ministry of Industry, Trade and Labor, 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 (20150909); and from the Morris Kahn Foundation. P.O. (Tel Aviv University) thanks the Naomi Foundation for the Global Research and Training Fellowship in Medical and Life Sciences. S.F. (Tel Aviv University) was partially funded by the Joseph Sagol President’s Ph.D. fellowship for neurosciences studies. R.H. was supported by the Bundesministerium für Bildung und Forschung (BMBF) within the Biotransporter Project (13N11536) and the Collaborative Research Center (SFB) 765. M.C. was supported by the Focus Area Nanoscale and the BMBF through NanoMatFutur Award 13N12561. The authors declare no conflicts of interest.

Publisher Copyright:
© 2018 FASEB. All rights reserved.


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


Dive into the research topics of 'Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma'. Together they form a unique fingerprint.

Cite this