Feinberg: In research published in Nature Medicine, Northwestern Medicine scientists have found a molecule that stops the growth of an aggressive pediatric brain tumor. Every year, about 300 children under the age of 10 years old in the U.S. develop the tumor, referred to as diffuse intrinsic pontine glioma (DIPG), which is always fatal. “This tumor kills every single kid who gets DIPG within one year. No one survives,” said the study’s first author, Andrea Piunti, PhD, a postdoctoral fellow in the lab of Ali Shilatifard, PhD, chair and Robert Francis Furchgott Professor of Biochemistry and Molecular Genetics.
“To the best of our knowledge, this is the most effective molecule so
far in treating this tumor,” said senior author Shilatifard. “Every
other therapy that has been tried so far has failed.”
Radiation therapy only prolongs patients’ survival by a few months, he noted.
Shilatifard’s lab previously identified the pathway through which
a mutation causes this cancer in studies with fruit flies,
research published in Science a few years ago.
He and colleagues believed the pathway would be a good target to
thwart the tumor and pushed forward with their molecular studies.
Shilatifard and Piunti collaborated with C. David James, PhD, professor of Neurological Surgery, Rintaro Hashizume, MD, PhD, assistant professor of Neurological Surgery, Craig Horbinski, MD, PhD, associate professor of Pathology and of Neurological Surgery, Rishi Lulla, MD, assistant professor of Pediatrics in the Division of Hematology, Oncology and Stem Cell Transplantation and Amanda Saratsis, MD,
assistant professor of Neurological Surgery. Lulla, a pediatric
neuro-oncologist, and Saratis, a pediatric neurosurgeon, respectively,
are also at the Ann & Robert H. Lurie Children’s Hospital of Chicago.
The scientists also are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
In a study with Hashizume’s group, they demonstrated that mice that
had the drug delivered through their abdomen had an increased survival
of 20 days, which is a long time in the life of a mouse, Piunti said.
Now the team at Northwestern Medicine and Lurie Children’s is working on
delivering the drug to the brain stem to see if the effect will be more
To test the molecule, scientists took tumor cell lines from a
pediatric patient who was untreated and injected those cells into the
brain stem of a mouse. The human tumor engrafted in the brain of the
mouse. The mouse was then treated with the molecule while scientists
monitored the tumor. The molecule stopped the growth of the tumor cells
and forced them to turn into other types of cells, known as
differentiation, thereby halting its growth.
This molecule detaches proteins, known as bromodomain proteins, from
their binding to a mutant protein, the histone H3K27M, which is present
in more than 80 percent of these tumors.
While the molecule itself is not yet available commercially, another
similar class of molecules, BET inhibitors, is being tested in clinical
trials for pediatric leukemia and other types of tumors. These could be
used in a clinical trial for the pediatric tumor, Piunti said.
The collaborative environment at Northwestern made the discovery possible, Shilatifard said.
“This work could not have been done anywhere in the world except
Northwestern Medicine, because of all the scientists and physicians who
have been recruited here during the past five years and how they work
together to link basic scientific research to the clinic,” Shilatifard
said. “This discovery is the perfect example of how we take basic
science discoveries and translate them to cure diseases at Northwestern
Shilatifard’s other Northwestern collaborators are Neil Kelleher, PhD, professor of Medicine in the division of Hematology/Oncology, and at the Weinberg College of Arts and Sciences; Elizabeth Bartom, PhD, assistant professor of Biochemistry and Molecular Genetics; Alexander Misharin, MD, PhD, assistant professor of Medicine in the Division of Pulmonary and Critical Care;
Marc Morgan, PhD; Stacy Marshall; Emily Rendleman; Quanhong Ma, PhD;
Yoh-hei Takahashi, PhD; Ashley Woodfin; and Nebiyu Abshiru, PhD.
The research was supported by grants RO1NS093079 and R35CA197569 from
the National Cancer Institute of the National Institutes of Health.