Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma
| العنوان: | Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma |
|---|---|
| المؤلفون: | Zvi Ram, Roni Blatt, Marcelo Calderón, Adva Krivitsky, Eylon Yavin, Rachel Grossman, Galia Tiram, Eytan Ruppin, Eilam Yeini, Orit Amsalem, Michael Milyavsky, Anat Eldar-Boock, Joo Sang Lee, Philip Lazarovici, Shiran Ferber, Jack Henkin, Rainer Haag, Dikla Ben-Shushan, Paula Ofek, Ronit Satchi-Fainaro, Nava Almog, Gadi Cohen |
| المصدر: | The FASEB Journal. 32:5835-5850 |
| بيانات النشر: | Wiley, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Small interfering RNA, Angiogenic Switch, Combination therapy, biology, business.industry, Cancer, medicine.disease, Biochemistry, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, In vivo, 030220 oncology & carcinogenesis, Genetics, medicine, Systemic administration, Cancer research, biology.protein, Dormancy, Epidermal growth factor receptor, business, Molecular Biology, Biotechnology |
| الوصف: | 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. |
| تدمد: | 1530-6860 0892-6638 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e7d21fd024f6d8e41f01eea51d353515 https://doi.org/10.1096/fj.201701568r |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e7d21fd024f6d8e41f01eea51d353515 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15306860 08926638 |
|---|