New plan of attack in fight against deadly childhood brain cancers

Researchers have devised a new plan of attack against a group of deadly childhood brain cancers collectively called diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), thalamic glioma and spinal cord glioma.

Scientists at the National Institutes of Health, Stanford University, California, and Dana-Farber Cancer Institute, Boston, identified a drug pair that worked together to both kill cancer cells and counter the effects of a genetic mutation that causes the diseases.

The researchers showed that combining the two drugs – panobinostat and marizomib – was more effective than either drug by itself in killing DMG patient cells grown in the laboratory and in animal models.

Their studies also uncovered a previously unrecognised vulnerability in the cancer cells that scientists may be able to exploit to develop new strategies against the cancer and related diseases. The results were published in Science Translational Medicine.

“Very few cancers can be treated by a single drug,” said Michelle Monje, a senior author of the study who treats children with DIPG and other diffuse midline gliomas.

“We’ve known for a long time that we would need more than one treatment option for DIPG. The challenge is prioritising the right ones when there are thousands of potential options. We’re hopeful that this combination will help these children.”

Monje and the National Cancer Institute’s Katherine Warren, now at Dana-Farber Cancer Institute and Boston Children’s Hospital, collaborated with Craig Thomas, and his colleagues at the NIH’s National Centre for Advancing Translational Sciences (NCATS). Thomas and his team used NCATS’ drug screening expertise and matrix screening technology to examine drugs and drug combinations to see which ones were toxic to DIPG patient cells.

NCATS’ robotics-enabled, high-throughput screening technologies enable scientists to rapidly test thousands of different drugs and drug combinations in a variety of ways. Scientists can examine the most promising single drugs and combinations, determine the most effective doses of each drug and learn more about the possible mechanisms by which these drugs act.

The NCATS researchers first studied the effects of single approved drugs and investigative compounds on DIPG cell models grown in the laboratory from patient cells. They focused on agents that could both kill DIPG cells and cross the brain’s protective blood-brain barrier, a necessity for a drug to be effective against DIPG in patients. The team then tested the most effective single agents in various combinations.

“Such large, complex drug screens take a tremendous collaborative effort,” said Thomas, also a senior study author.

“NCATS was designed to bring together biologists, chemists, engineers and data scientists in a way that enables these technically challenging studies.”

While there were multiple, promising outcomes from these screens, the team focused on the combination of histone deacetylase inhibitors (like panobinostat) with drugs called proteasome inhibitors (such as marizomib). Proteasome inhibitors block cells’ normal protein recycling processes.

The panobinostat-marizomib combination was highly toxic to DIPG cells in several models, including DIPG tumour cell cultures that represented the main genetic subtypes of the disease and mice with cells transplanted from patient tumours.

The combination also reduced tumour size in mice and increased their survival. A similar response was found in spinal cord and thalamic DMG models developed from cells grown in culture from patient cells.

The screening studies also provided important clues to the ways the drugs were working. Building on these data, the collaborative team subsequently conducted a series of experiments that showed the DIPG cells responded to these drugs by turning off a biochemical process in the cell’s mitochondria that is partly responsible for creating ATP, which provides energy to cells. The drug combination essentially shuts down tumour cell ATP production.

“The panobinostat-marizomib drug combination exposed an unknown metabolic vulnerability in DIPG cells,” said first author Grant Lin 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.”

Plans are underway for clinical trials of the drug combination and of marizomib alone.

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