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Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma
Author(s) -
Tiram Galia,
Ferber Shiran,
Ofek Paula,
Eldar-Boock Anat,
Ben-Shushan Dikla,
Yeini Eilam,
Krivitsky Adva,
Blatt Roni,
Almog Nava,
Henkin Jack,
Amsalem Orit,
Yavin Eylon,
Cohen Gadi,
Lazarovici Philip,
Lee Joo Sang,
Ruppin Eytan,
Milyavsky Michael,
Grossman Rachel,
Ram Zvi,
Calderón Marcelo,
Haag Rainer,
Satchi-Fainaro Ronit
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201701568r
Subject(s) - cancer research , dormancy , biology , epidermal growth factor receptor , glioma , malignancy , cancer , in vivo , medicine , genetics , botany , germination
Glioblastoma is an aggressive and invasive brain malignancy with high mortality rates despite 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. EGFR up‐regulation was reversed using EGFR small interfering RNA polyplex, antibody, or small‐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, in 3‐dimensional patient‐derived spheroids, and in a subcutaneous human glioblastoma model in vivo. Systemic administration of the combination therapy to mice bearing intracranial murine glioblastoma resulted in marginal 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 glioblastoma therapy. This therapeutic strategy can be exploited for future investigations using a variety of therapeutic entities that manipulate the expression of dormancy‐associated genes in glioblastoma as well as in other cancer types.—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., Calderón, M., Haag, R., Satchi‐Fainaro, R. Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma. FASEB J. 32, 5835–5850 (2018). www.fasebj.org