Evidence map›Paper›PMID 29113289›Full record

ArticleOncotarget2017

Synergistic and targeted therapy with a procaspase-3 activator and temozolomide extends survival in glioma rodent models and is feasible for the treatment of canine malignant glioma patients.

Avadhut D Joshi, Rachel C Botham, Lisa J Schlein, Howard S Roth, Antonella Mangraviti, Alexandra Borodovsky, Betty Tyler, Steve Joslyn, Jayme S Looper, Michael Podell and 3 more

Open access · diamondAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed, 1 pooled it
3.4field-weighted citation impact, top 7% 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, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.

  1. Pooled it
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  18. New imidazo[2,1-RSC medicinal chemistry · 2020
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 4 institutions in 1 country.

Avadhut D Joshi *Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Rachel C Botham *Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Lisa J SchleinDepartment of Pathobiology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Howard S RothDepartment of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Antonella MangravitiDepartment of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Alexandra BorodovskyDepartment of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Betty TylerDepartment of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Steve JoslynVetCT Australia, Fremantle WA, Australia.
Jayme S LooperDepartment of Veterinary Clinical Sciences, Louisiana State University, Baton Rouge, LA, USA.
Michael PodellDepartment of Neurology, MedVet Chicago, Chicago, IL, USA.
Timothy M FanDepartment of Veterinary Clinical Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Paul J HergenrotherDepartment of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Gregory J RigginsDepartment of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
University of Illinois Urbana-Champaign · USJohns Hopkins University · USJohns Hopkins Medicine · USLouisiana State University · US

Funding

Small Molecule Activators of Procaspases as Anti-Cancer AgentsR01CA120439 · NCI · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · PI HERGENROTHER, PAUL · 2007 to 2022
$6.2M
Training Program in Chemistry-Interface with BiologyT32GM070421 · NIGMS · UNIVERSITY OF ILLINOIS URBANA-CHAMPAIGN · PI HERGENROTHER, PAUL · 2005 to 2019
$5.4M
Optimizing demethylating therapy for IDH1 Mutant Malignant GliomasR01CA190223 · NCI · JOHNS HOPKINS UNIVERSITY · PI RIGGINS, GREGORY JOSEPH · 2015 to 2024
$3.4M
NCI NIH HHS R01 CA120439NCI NIH HHS R01 CA190223NIGMS NIH HHS T32 GM070421
6 · The paper itself

Abstract

purposeGlioblastoma is a deadly brain cancer with a median survival time of ∼15 months. Ionizing radiation plus the DNA alkylator temozolomide (TMZ) is the current standard therapy. PAC-1, a procaspase-3 activating small molecule, is blood-brain barrier penetrant and has previously demonstrated ability to synergize with diverse pro-apoptotic chemotherapeutics. We studied if PAC-1 could enhance the activity of TMZ, and whether addition of PAC-1 to standard treatment would be feasible in spontaneous canine malignant gliomas. EXPERIMENTAL

designUsing cell lines and online gene expression data, we identified procaspase-3 as a potential molecular target for most glioblastomas. We investigated PAC-1 as a single agent and in combination with TMZ against glioma cells in culture and in orthotopic rodent models of glioma. Three dogs with spontaneous gliomas were treated with an analogous human glioblastoma treatment protocol, with concurrent PAC-1.

resultsProcaspase-3 is expressed in gliomas, with higher gene expression correlating with increased tumor grade and decreased prognosis. PAC-1 is cytotoxic to glioma cells in culture and active in orthotopic rodent glioma models. PAC-1 added to TMZ treatments in cell culture increases apoptotic death, and the combination significantly increases survival in orthotopic glioma models. Addition of PAC-1 to TMZ and radiation was well-tolerated in 3 out of 3 pet dogs with spontaneous glioma, and partial to complete tumor reductions were observed.

conclusionsProcaspase-3 is a clinically relevant target for treatment of glioblastoma. Synergistic activity of PAC-1/TMZ in rodent models and the demonstration of feasibility of the combined regime in canine patients suggest potential for PAC-1 in the treatment of glioblastoma.

Indexed as

glioblastomaPAC-1procaspase-3 activatorsmall molecule therapy

Identifiers

PMID29113289
PMCPMC5655184
OpenAlexW2726121999

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.