Preclinical Study Points to Possible Treatment for Lethal Pediatric Brain Cancer


Key Points

  • Diffuse intrinsic pontine glioma (DIPG), a particularly lethal form of pediatric brain cancer, has a 5-year survival rate of less than 1%.
  • Panobinostat inhibited the growth of 12 out of 16 DIPG cell lines; it also inhibited tumor growth and extended survival in DIPG mouse models.
  • Combining panobistat and GSKJ4, a drug that blocks the removal of methyl groups from histones, appeared to slow tumor growth even further.

Using brain tumor samples collected from children in the United States and Europe, an international team of scientists found that the drug panobinostat (Farydak) and similar gene-regulating drugs may be effective at treating diffuse intrinsic pontine glioma (DIPG), an aggressive and lethal form of pediatric cancer. The results were published by Grasso et al in Nature Medicine.

“Our results provide a glimmer of hope for treating this heartbreaking disease,” said Michelle Monje, MD, PhD, Assistant Professor of Neurology and Neurological Sciences at Stanford University School of Medicine, a specialist in DIPG.

About DIPG

DIPG is typically diagnosed in children 4 to 9 years of age. Children progressively lose muscle control as the cancer rapidly attacks the pons, a region deep inside the brain that connects the brain to the spinal cord, and is difficult to reach and surgically remove. Despite radiation treatment, children usually survive for about 9 months, with less than 1% surviving longer than 5 years.

Six years ago, Dr. Monje started to create and share cell cultures of patients’ DIPG cells that could be studied in laboratories. In this study, she and her colleagues used cell cultures collected from 16 patients in the United States and Europe to search for drugs that could kill or stop the growth of DIPG cells. By performing experiments in petri dishes and with mice, they found that panobinostat may be effective at inhibiting DIPG growth and extending survival rates.

“It's astounding. In only 6 years, scientists have gone from knowing virtually nothing about this tumor to understanding its underlying genetics and finding a potential therapy,” said Jane Fountain, PhD, Program Director at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH).

Study Details

The researchers began their work by performing high-throughput screening experiments, an advanced method for rapidly searching for effective compounds. The screening simultaneously tested 83 known or potential cancer drugs on each of the DIPG cell lines. They found that histone deacetylase inhibitors consistently slowed DIPG growth. Several of these drugs block histone deacetylases, a group of enzymes that regulate genes by removing chemical tags, called acetyl groups, from histone proteins. The scientists saw similar results when they genetically blocked individual histone deacetylases in the DIPG cells.

The scientists also analyzed the genes of each cell line. After reviewing the genetic and screening data they decided to focus on panobinostat, a drug designed to block multiple types of histone deacetylases. In petri dishes, they showed that panobinostat inhibited the growth of 12 out of 16 DIPG cell lines. When the scientists placed DIPG cells in the pons area of mice, they found that systemic injections of panobinostat inhibited DIPG growth and extended survival.

“All roads lead to histones,” said Dr. Monje. “Our results support the idea that histone modifications are the keys to understanding and treating DIPG.”

Potential Therapeutic Strategy

Located in a cell's nucleus, histones are protein complexes that act like genetic spools wound with genes on chromosomes. Enzymes, including histone deacetylases, influence how chromosomes wind around histones by adding or removing chemical tags. In turn, the tagging epigenetically controls whether a gene on a chromosome will be expressed in that cell.

The scientists showed that panobistat may be effective at treating a variety of DIPG tumors. Approximately 80% of DIPG tumors have a specific mutation in a histone gene, H3K27M. This mutation blocks the ability of methyltransferase from adding a chemical tag, called a methyl group, to the histone. Although the H3K27M mutation disrupts a different chemical-tagging system, the scientists showed that panobinostat slowed the growth of a line of cells that had the mutation. Panobinostat also slowed the growth of DIPG cells that do not have that mutation.

Finally, the scientists showed that panobinostat may work in combination with other treatments. Studying H3K27M cells that developed resistance to panobinostat over time, they showed that GSKJ4, a drug that blocks the removal of methyl groups from histones, slowed tumor growth. Combining panobistat and GSKJ4 appeared to slow growth further, suggesting the two compounds work synergistically.

“This may be a first step to finally improving the prognosis of this seemingly untreatable disease,” said Dr. Monje.

Dr. Monje, together with the National Cancer Institute-supported Pediatric Brain Tumor Consortium and Novartis, is planning to conduct clinical trials to test the safety and effectiveness of panobinostat for children with DIPG.

Dr. Monje and Charles Keller, MD, of the Children’s Cancer Therapy Development Institute, are the corresponding authors for the Nature Medicine article.

The study was supported by grants from the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, the DIPG Collaborative, and Accelerate Brain Cancer Cures Foundation, among others.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.