Researchers have tested a new drug combination that shows promise for the treatment of several types of childhood brain cancers known as diffuse midline gliomas (DMG). The research was published in the journal Science Translational Medicine.
The cancers include diffuse intrinsic pontine glioma (DIPG), thalamic glioma and spinal cord glioma. They are aggressive and hard to treat and typically affect a few hundred children annually between the ages of 4 to 12. The children typically die within a year of diagnosis. DMGs are usually the result of a specific mutation in histone genes. Histones are proteins that DNA twists around to form chromatin. DNA winds and unwinds around histones, and how that functions is influenced by histone deacetylases and other enzymes. These enzymes are also involved in epigenetic signaling, which turns genes on and off.
The researchers worked with two drugs, panobinostat and marizomib, in cell cultures and animal models. The research was conducted by Michele Monje, a neuro-oncologist at Stanford University, Katherine Warren, formerly with the National Cancer Institute, but now with the Dana-Farber Cancer Institute and Boston Children’s Hospital, and Craig Thomas and his group at the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS).
“Very few cancers can be treated by a single drug,” said 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.”
In early research, Monje and her team demonstrated that panobinostat, a drug that blocks key histone deacetylase enzymes, could restore DIPG histone function. It is in early clinical testing in DIPG patients, but the researchers believe its usefulness will be limited because cancer cells show adaptation and resistance to single therapeutics. Thomas and his group leveraged NCATS’ drug screening expertise and matrix screening technology to screen drugs and drug combinations to determine the ones most toxic to DIPG cells.
The NCATS technologies includes robotic, high-throughput screening to rapidly test thousands of different drugs and drug combinations. The NCATS team began by looking at single approved drugs and experimental molecules on DIPG cell models grown in Petri dishes. The initial focus was on compounds that both kill DIPG cells and cross the blood-brain barrier. They then evaluated the most effective single drugs in combinations.
“Such large, complex drug screens take a tremendous collaborative effort,” Thomas said. “NCATS was designed to bring together biologists, chemists, engineers and data scientists in a way that enables these technically challenging studies.”
Panobinostat is a histone deacetylase inhibitor. Marizomib is a proteasome inhibitor. Proteasome inhibitors block the normal protein recycling processes in cells. The combination of the two drugs was very toxic to DIPG cells in several models, including DIPG tumor cell cultures that are the most common genetic subtype of the disease. In mice, the drug combination decreased tumor size and increased survival. Responses were similar in DMG models in spinal cord and thalamic cancers.
The research team was also able to determine how this combination worked, shutting off a biochemical process in the mitochondria that is responsible for creating ATP, which produces energy in cells. The combination shut down cancer cell ATP production.
“The panobinostat-marizomib drug combination exposes an unknown metabolic vulnerability in DIPG cells,” said Grant Lin, first author of the study, a researcher at Stanford. “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.”
They are now working to design clinical trials for the drug combination and for marizomib alone.