Brain Tumor in Children: New Therapy Target Offers Hope

Restoring a tumor suppressor gene p16 could be a promising new target for treating a brain tumor, finds a new study from the Ann & Robert H. Lurie Children's Hospital of Chicago. The new study published in the Molecular Cancer Research has revealed that the tumor suppressor gene p 16 can be turned off by a histone mutation and is found to be responsible for up to 70% of the childhood brain tumors called Diffuse Intrinsic Pontine Glioma (DIPG).

The researchers also have demonstrated that this could be accomplished invitro by using a drug that is approved for treating adult leukemia and other cancers.

Dr. Oren J. Becher, from Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago, said, "Using a genetic mouse model of DIPG, we found that the histone mutation turns off p16, which is a gene that acts like a break on dividing cells."

"When p16 is repressed, cells can divide faster, which gives rise to a tumor. We also found that in DIPG, the histone mutation cooperates with overactive growth factor (called PDGF) signaling, which further accelerates brain stem tumor formation."

In Vitro Activity
The research team discovered that in vitro the p 16 gene could be turned back on using a drug that could inhibit DNA methylation.

The mechanism has been found to act as an off switch for the gene. The study results were found to restore p16 function that could slow down the tumor growth.

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What is a Histone?
Histone is a protein that could act like a spool for DNA. This could help to pack the six-foot long DNA strand in the tiny nucleus of each cell. The histone proteins are also capable of regulating which gene would turn on and off, by a process that could go wrong when there is an histone mutation.

Therefore, the discovery of histone mutation in 2012 could open up a new line of research that could find new treatment targets.

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Becher, the Rory David Deutsch Scholar oncologist at Lurie Children’s, as well as Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine, said, "This was an unexpected finding."

"We first tried a histone methylation inhibitor -- a promising new class of cancer drugs -- but that did not restore p16 or had any effect on tumor growth. But when we used a DNA methylation inhibitor, it worked. We now have early evidence that targeting DNA methylation may be useful in restoring p16, and thereby arresting tumor growth. We need more research to confirm this finding in animal models before studying this strategy in children with DIPG. This is incremental progress."

Diffuse Intrinsic Pontine Glioma (DIPG)
This is a most deadly brain tumor in children that has no approved drugs for treatment. The latest advancement for treatment was with the introduction of radiation therapy that could temporarily decrease symptoms and however does not cure DIPG.

Facts on DIPG

• Around 10-15% of the brain tumors in children are due to DIPG
• DIPG is the most common cause of death due to the brain tumor in children
• There is no definite known cause for DIPG
• Mostly the tumor is diagnosed at the age of 5 and 7 years
• The average survival of DIPG patients would be less than one year after diagnosis of the tumor

References

1. Francisco J. Cordero, Zhiqing Huang, Carole Grenier, Xingyao He, Guo Hu, Roger E. McLendon, Susan K Murphy, Rintaro Hashizume and Oren J Becher et.al, 'Histone H3.3K27M represses p16 to accelerate gliomagenesis in a murine model of DIPG,' Molecular Cancer Research (2017); DOI: 10.1158/1541-7786.MCR-16-0389
2. Facts About Pediatric Cancer - (http://courageforcures.org/resources/fast-facts/)
3. Diffuse Intrinsic Pontine Glioma (DIPG) - ( http://www.danafarberbostonchildrens.org/conditions/brain-tumor/diffuse-pontine-glioma.aspx)

Source-Medindia