A study published in Nature Communications found that an inhibitor of an enzyme called ACVR1 slows tumor growth and increases survival in an animal model of diffuse intrinsic pontine glioma (DIPG) - the most deadly brain tumor in children. Currently, there are no approved drugs for treating DIPG. This research opens the door to a promising new treatment strategy.
"Our results are encouraging and suggest that it might be reasonable to test an inhibitor of this enzyme in a clinical trial," says senior author. "Prior to that, we need to evaluate different ACVR1 inhibitors in animal models to make sure we bring the most safe and effective agent to trials with children."
In 2014, Dr. Becher's lab co-discovered that ACVR1 mutations are found in approximately 25 percent of DIPGs, leading the enzyme to be overactive. In the current study, the lab demonstrates for the first time in an animal model that this enzyme mutation cooperates with a histone mutation (H3.1 K27M) found in 20 percent of DIPGs. Together, these mutations are important in initiating tumor development.
Histone is a protein that acts like a spool for DNA, helping to package the six-foot long DNA strand into the tiny nucleus of every cell. Histones also help regulate which genes turn on and off, a process that goes awry when there is a histone mutation.
Authors show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis.
However, in combination with PDGFA signaling, ACVR1R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment.
"Our future work will examine why and how the ACVR1 and histone mutations work together to trigger DIPG development," says the senior author. "Greater insight into this process will bring us closer to identifying a successful therapy for children with DIPG."
https://www.nature.com/articles/s41467-019-08823-9
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Facvr1-r206h-cooperates&filter=22
Slowing the glioma growth!
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