Children's Health

A Promising Discovery for Childhood Cancer?

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 (NIH); Stanford University, California; and Dana-Farber Cancer Institute, Boston, identified two drugs that worked together to both kill cancer cells and counter the effects of a genetic mutation that causes the diseases. Combining panobinostat and marizomib was more effective than either drug by itself in killing DMG patient cells grown in the laboratory and in animal models, the researchers said. Their studies also uncovered a previously unrecognized 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 Nov. 20 in Science Translational Medicine, according to a news release from NIH.

DMGs are aggressive, hard-to-treat tumors that represent the leading cause of brain cancer-related death among U.S. children. DMGs typically affect a few hundred children a year between ages 4 to 12; most children die within a year of diagnosis. Most cases are caused by a specific gene mutation.


In an earlier study, Stanford neuro-oncologist Michelle Monje. M.D., Ph.D., and her colleagues showed that panobinostat could restore the DIPG mutation to a more normal state. While panobinostat is already in early clinical testing in DIPG patients, its usefulness may be limited because cancer cells can learn to evade its effects.

So Monje’s team wanted to identify other drugs – and combinations of them – that could affect the cancer.  “Very few cancers can be treated by a single drug,” said 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 prioritizing 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, M.D., now at Dana-Farber Cancer Institute and Boston Children’s Hospital, collaborated with Craig Thomas, Ph.D., and his colleagues at the NIH’s National Center 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.

The screening technology they used 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.

“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.”

The screening studies also provided important clues to the ways the drugs were working.  As a result, the collaborative team subsequently conducted a series of experiments that showed the DIPG cells responded to panobinostat and marizomib by turning off a biochemical process that shuts down malevolent growth in cell energy.

Monje stressed the panobinostat-marizomib combination might be an important component of a multitherapy strategy, including approaches that harness the immune system and those that disrupt factors in the tumor “microenvironment” that cells depend on to grow. Like Warren, Monje emphasized the need to better understand how drugs target and impact the DIPG cells’ vulnerabilities.

“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. We want to move past this guesswork and provide preclinical evidence to guide clinical decisions and research directions.”

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


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