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The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma.
- Source :
-
Journal of hematology & oncology [J Hematol Oncol] 2018 Feb 27; Vol. 11 (1), pp. 32. Date of Electronic Publication: 2018 Feb 27. - Publication Year :
- 2018
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Abstract
- Background: The use of alkylating agents such as temozolomide in association with radiotherapy (RT) is the therapeutic standard of glioblastoma (GBM). This regimen modestly prolongs overall survival, also if, in light of the still dismal prognosis, further improvements are desperately needed, especially in the patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors, in which the benefit of standard treatment is less. Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor (AK-DACi) molecule that fuses the DNA damaging effect of bendamustine with the fully functional pan-histone deacetylase (HDAC) inhibitor, vorinostat, in a completely new chemical entity.<br />Methods: Tinostamustine has been tested in models of GBM by using 13 GBM cell lines and seven patient-derived GBM proliferating/stem cell lines in vitro. U87MG and U251MG (MGMT negative), as well as T98G (MGMT positive), were subcutaneously injected in nude mice, whereas luciferase positive U251MG cells and patient-derived GBM stem cell line (CSCs-5) were evaluated the orthotopic intra-brain in vivo experiments.<br />Results: We demonstrated that tinostamustine possesses stronger antiproliferative and pro-apoptotic effects than those observed for vorinostat and bendamustine alone and similar to their combination and irrespective of MGMT expression. In addition, we observed a stronger radio-sensitization of single treatment and temozolomide used as control due to reduced expression and increased time of disappearance of γH2AX indicative of reduced signal and DNA repair. This was associated with higher caspase-3 activation and reduction of RT-mediated autophagy. In vivo, tinostamustine increased time-to-progression (TTP) and this was additive/synergistic to RT. Tinostamustine had significant therapeutic activity with suppression of tumor growth and prolongation of DFS (disease-free survival) and OS (overall survival) in orthotopic intra-brain models that was superior to bendamustine, RT and temozolomide and showing stronger radio sensitivity.<br />Conclusions: Our data suggest that tinostamustine deserves further investigation in patients with glioblastoma.
- Subjects :
- Animals
Antineoplastic Agents, Alkylating pharmacology
Bendamustine Hydrochloride pharmacology
Bendamustine Hydrochloride therapeutic use
Benzimidazoles pharmacology
Brain Neoplasms pathology
Cell Line, Tumor
Female
Glioblastoma pathology
Histone Deacetylase Inhibitors pharmacology
Humans
Mice
Vorinostat pharmacology
Vorinostat therapeutic use
Antineoplastic Agents, Alkylating therapeutic use
Benzimidazoles therapeutic use
Brain Neoplasms drug therapy
Brain Neoplasms radiotherapy
Glioblastoma drug therapy
Glioblastoma radiotherapy
Histone Deacetylase Inhibitors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1756-8722
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of hematology & oncology
- Publication Type :
- Academic Journal
- Accession number :
- 29486795
- Full Text :
- https://doi.org/10.1186/s13045-018-0576-6