Restoring a tumor suppressing gene offers a promising therapeutic target for diffuse intrinsic pontine glioma.
Reactivating the tumor suppressor gene p16 may serve as a potential therapeutic option for pediatric patients with diffuse intrinsic pontine glioma (DIPG).
Histones help regulate which genes are turned on and off, but when it becomes mutated, its role becomes skewed.
In patients with DIPG, the p16 tumor suppressor gene is turned off by the histone mutation H3.3K27M, which is found in up to 70% of DIPG tumors.
In a study published in Molecular Cancer Research, investigators used a genetic mouse model of DIPG to examine this process.
“We found that the histone mutation turns off p16, which is a gene that acts like a break on dividing cells,” said senior author Oren J. Becher, MD. “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 [PDGF] signaling, which further accelerates brain stem tumor formation.”
Most promising, the investigators found that the p16 gene can be turned back on in vitro using a drug that inhibits DNA methylation. The results of the study showed that restoring p16 function slowed tumor growth.
“This was an unexpected finding,” Becher said. “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.”
Although DIPG is the deadliest brain tumor among children, there is currently no FDA-approved drugs on the market to treat the disease. In the 1960s, the introduction of radiation therapy temporarily decreased symptoms but failed to cure DIPG.