Evidence map›Paper›PMID 29486795›Full record

ArticleJournal of hematology & oncology2018

The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma.

Claudio Festuccia, Andrea Mancini, Alessandro Colapietro, Giovanni Luca Gravina, Flora Vitale, Francesco Marampon, Simona Delle Monache, Simona Pompili, Loredana Cristiano, Antonella Vetuschi and 3 more

Erratum issuedOpen access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of hematology & oncology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 28 papers.

0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed
5.2field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

28 citing papers in PubMed, 57 citations in OpenAlex.

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  13. ProNGF Expression and Targeting in Glioblastoma Multiforme.International journal of molecular sciences · 2023
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors at 2 institutions in 1 country.

Claudio FestucciaLaboratory of Radiobiology, Department of Applied Clinical Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy. claudio.festuccia@univaq.it.
Andrea ManciniLaboratory of Radiobiology, Department of Applied Clinical Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy.
Alessandro ColapietroLaboratory of Radiobiology, Department of Applied Clinical Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy.
Giovanni Luca GravinaLaboratory of Radiobiology, Department of Applied Clinical Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy.
Flora VitaleDivision of Neurosciences, Department of Applied Clinical Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy.
Francesco MaramponDivision of Radiotherapy, Department of Applied Clinical Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy.
Simona Delle MonacheDivision of Applied Biology, Department of Applied Clinical Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy.
Simona PompiliDivision of Human Anatomy, Department of Applied Clinical Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy.
Loredana CristianoLaboratory of Applied Biology, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
Antonella VetuschiDivision of Human Anatomy, Department of Applied Clinical Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy.
Vincenzo TomboliniDivision of Radiotherapy, Department of Experimental Medicine, University of Rome "La Sapienza", Rome, Italy.
Yi ChenNorthlake International LLC, Pleasanton, CA, USA.
Thomas MehrlingMundipharma-EDO GmbH, Basel, Switzerland.
University of L'Aquila · ITSapienza University of Rome · IT

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundThe 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.

methodsTinostamustine 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.

resultsWe 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.

conclusionsOur data suggest that tinostamustine deserves further investigation in patients with glioblastoma.

Indexed as

AnimalsAntineoplastic Agents, AlkylatingBendamustine HydrochlorideBenzimidazolesBrain NeoplasmsCell Line, TumorFemaleGlioblastomaHistone Deacetylase InhibitorsHumansMiceVorinostatAntineoplastic Agents, AlkylatingBendamustine HydrochlorideBenzimidazolesHistone Deacetylase InhibitorstinostamustineVorinostatBendamustineGlioblastomaRadio sensitivityTinostamustineVorinostat

Identifiers

PMID29486795
PMCPMC5830080
OpenAlexW2791396154

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.