Vital Signs » Summer 2018
There are many battles that Robert Lober, M.D., Ph.D., has faced as a physician. But perhaps none have been so trying as his fight against a deadly type of childhood brain tumor.
“For me, it’s not just academic interest. We are fighting a heartbreaking disease that affects my patients at Dayton Children’s Hospital,” said Lober, an assistant professor of pediatrics at the Wright State University Boonshoft School of Medicine. “You only have to see one child with this to realize that the lack of viable treatment options is a crisis.”
Lober has been working to study the tumor for years. It is known clinically as a diffuse intrinsic pontine glioma (DIPG) and is so difficult to treat because of its location within the brainstem. Surgery is not an option for treatment because of the risk for catastrophic neurological injury.
“Radiation therapy and chemotherapy may temporarily relieve some symptoms,” Lober said. “But even after more than 250 clinical trials with these treatments, none have improved survival for our patients.”
To help fight this horrible tumor, Lober and others are working to discover how it spreads. Unraveling its mysteries will not only increase the potential for better treatments, but also possibly improve the fundamental understanding of human biology.
This tumor is the first known to have an epigenetic cause. It develops from an error in the normal mechanisms for repressing certain genes, and is passed from cell to cell in a way that is outside the DNA sequence. Because of its rare origins, it is difficult for researchers to find tissue for study.
“Each cultured tumor we have came from a child at the time of autopsy,”
Lober said. “Each was a precious gift from the child’s parent, a way to maybe help the next family stricken by this.”
There is much left to discover, but Lober has some knowledge of the tumor’s development. Its histone proteins, which are tiny spools that organize DNA and regulate gene transcription, first acquire a mutation. The mutation only impacts about 5 percent of the histone proteins within a cell, but it affects the way all of the cell’s histones work. This impacts the expression of countless genes.
He and his fellow investigators hope to identify the most important alterations and target them with new treatment strategies. So far, they have narrowed their scope to three genes that may normally work to suppress tumor formation. These become silenced amidst the histone mutation.
By infecting the DIPG cells with viruses that are artificially engineered to control the expression of the three particular genes, the idea is to block the effects of the mutated histone protein if it relies on the genes to promote tumor cell division, migration, or brain invasion.
“We are talking about disrupting a process that’s been in place for more than 1 billion years of evolution in every animal type that exists. One would think that absolute chaos would ensue and kill the cells but, instead, the cells institute compensatory processes that we do not understand,” Lober said. “The result is the worst tumor I have ever dealt with as a doctor. There is no higher priority for me.”
Several other laboratories are deciphering the workings of this deadly brain tumor. Most of their efforts have looked at only one of the genes, Cdkn2a, which encodes proteins that stop tumor growth.
“For every cell function, there are many partner proteins acting in concert,” Lober said. “Our study could determine if this gene is a critical driver or just a passenger in this story.”
Lober’s study, funded by the Mayfield Education and Research Foundation, is considering two other genes involved in the process. They are believed to have roles in cell differentiation and migration during embryonic development. By including them in the study, Lober and colleagues may learn new information about cancer as well as normal brain development.
The investigation is still underway, and it is too early to draw conclusions. But the insights so far are encouraging.
“We are starting to learn the nuances of DIPG growth and expression of these genes in specific culture conditions and after certain drug treatments,” Lober said. “Everything must be repeated numerous times with reliable results before we can fully describe our observations.”
Other efforts are also underway to fight this tumor. Large, international studies have the best technologies and funding and may one day uncover a cure. Lober wants to do his part by drawing upon local resources and talent in Dayton.
“When it comes to this crisis, I will speak to anyone who will listen, and I will collaborate with anyone who can bring a new skill set into the fight,” Lober said.
— Daniel Kelly