Scientists used studies on cell and animal models to reveal insights into lethal childhood brain cancers and find promising drug therapeutics. The deadly childhood brain cancers, often referred to as diffuse midline gliomas (DMG), include intrinsic pontine glioma (DIPG), thalamic glioma and spinal cord glioma. DMGs are challenging to treat and thus represent the leading cause of brain cancer-related death among U.S. children with most children passing away within a year of diagnosis. Most DMG patients have the diagnosis are a result of a genetic mutation in how DNA packages itself in the nucleus.
Now, a collaborative team of researchers found that combining two drugs – panobinostat and marizomib – was effective in killing these lethal brain cells and counter the effect of the genetic mutation that serves as the culprit for the disease.
“Such large, complex drug screens take a tremendous collaborative effort,” said Craig Thomas, a senior study author. “The NIH’s National Center for Advancing Translational Sciences (NCATS) was designed to bring together biologists, chemists, engineers and data scientists in a way that enables these technically challenging studies.”
The findings of the study were published in Science Translational Medicine.
“The panobinostat-marizomib drug combination exposed an unknown metabolic vulnerability in DIPG cells,” said first author Grant Lin, Ph.D., at Stanford University School of Medicine. “We didn’t expect to find this, and it represents an exciting new avenue to explore in the development of future treatment strategies for diffuse midline gliomas.”
NCATS.com (credit): Confocal micrograph of diffuse intrinsic pontine glioma (DIPG) cells, grown from patient cells, in culture. Image Credit: Shawn Gillespie, Thomas Monje Lab
“Very few cancers can be treated by a single drug,” says Stanford neuro-oncologist and also a senior author of the study, Michelle Monje. “We’ve known for a long time that we would need more than one treatment option for DIPG. The challenge is prioritizing the right ones when there are thousands of potential options. We’re hopeful that this combination will help these children.”
The drug combination was highly effective at eradication of tumor cells because of its potent toxicity to the main genetic subtypes of the disease. One of the drugs, panobinostat, is a histone deacetylase inhibitor, and the other marizomib, is a proteasome inhibitor that blocks a cells ability to recycle its proteins. Researchers tested the multi-therapeutic strategy on several genetic models as well as in mice with transplanted cells from patient tumors.
“Our work with NCATS showed the need to gather more preclinical data in a systematic, high-throughput way to understand and prioritize the strategies and agents to combine,” Monje said. “Otherwise we’re testing things one or two drugs at a time and designing clinical trials without preclinical data based on hypothesized mechanisms of action. We want to move past this guesswork and provide preclinical evidence to guide clinical decisions and research directions.” Lin added, “The idea is to get as many effective tools as possible to work with that can have an impact on patients.”