Every year in the United States, several hundred children and their families receive a devastating diagnosis: diffuse intrinsic pontine glioma (DIPG). Sadly, this inoperable tumor of the brain stem, little known by the public, is almost always fatal, and efforts to develop life-saving treatments have been hampered by a lack of molecular data to identify agents that might specifically target DIPG. In fact, more than 200 clinical trials of potential drugs have been conducted in DIPG patients without any success.
Now, using cell lines and mouse models created with tumor tissue donated by 16 DIPG patients, an international research coalition has gained a deeper understanding of this childhood brain cancer at the molecular level. These new preclinical tools have also opened the door to identifying more precise targets for DIPG therapy, including the exciting possibility of using a drug already approved for another type of cancer.
The latest work was performed at 13 institutions in the United States, France, Canada, and The Netherlands. In addition to its groundbreaking science, this coalition is to be commended for the creative way in which it pulled together researchers from a wide range of disciplines, along with financial support from both the public and non-profit sectors. Besides NIH, the coalition received funding from the National Science Foundation, Department of Defense, Lyla Nsouli Foundation, Children’s Oncology Group, DIPG Collaborative, Accelerate Brain Cancer Cures Foundation, CureSearch for Childhood Cancer, Team Julian Foundation, and many other non-profit organizations.
In their study published in Nature Medicine , the researchers report that panobinostat—a drug that the Food and Drug Administration (FDA) recently approved to treat multiple myeloma —also slows the growth of DIPG cell lines grown in lab dishes. What’s more, panobinostat improved survival in mice with DIPG tumors implanted in their brains.
Panobinostat is a new type of drug that works by blocking an enzyme responsible for modifying DNA at the epigenetic level. Epigenetics refers to chemical marks on DNA itself or on the protein “spools” called histones that package DNA. These marks influence the activity of genes without changing the underlying sequence, essentially acting as volume knobs for genes.
Earlier genomic studies showed that about 80 percent of DIPG tumors carry a mutation that alters a histone protein, resulting in changes to the way DNA is packaged and tagged with those chemical marks. This faulty epigenetic regulation results in activation of growth-promoting genes that should have been turned off, and shutdown of others that should have acted as brakes to cell multiplication. Cancer is the result. Panobinostat appears to work by restoring proper functioning of the cells’ chemical tagging system.
Zeroing in on panobinostat was no small task. The team, led by Michelle Monje of Stanford University School of Medicine, Palo Alto, CA, and Charles Keller of the Children’s Cancer Therapy Development Institute, Fort Collins, CO, started out with a group of 83 compounds selected for possible activity against DIPG by pediatric neuro-oncologists. Using cells cultured from the DIPG patients, researchers screened the 83 compounds for their cancer-fighting ability and found that 14 showed some ability to slow the cells’ growth. Ultimately, the team’s careful molecular analysis of the treated cells, along with earlier genomic evidence, pointed to panobinostat as the drug with the most potential for DIPG treatment.
The researchers expect to launch a clinical trial to test the safety of panobinostat in DIPG patients within the year, via the NIH-funded Pediatric Brain Tumor Consortium. For a disease in which survival is currently measured in months, the hope is that this drug may represent a first step towards effective, life-extending treatments for children stricken by DIPG.
Still, researchers caution that panobinostat by itself probably won’t be a cure. When treated with a single targeted drug, cancer cells almost inevitably develop resistance. Researchers have already witnessed this in DIPG cells treated with panobinostat in a lab dish. However, these experiments also suggested that addition of a second epigenetic drug may help.
Among the near-term goals of the Precision Medicine Initiative are the development and testing of precise new combinations of treatments for many types of cancer, both adult and pediatric. Indeed, this new study on DIPG serves as yet another concrete reminder of the gains that can be made as fundamental research moves us toward more precise approaches of preventing and treating cancer and a great many other diseases.
 Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily MA, Quist MJ, Davis LE, Huang EC, Woo PJ, Ponnuswami A, Chen S, Johung TB, Sun W, Kogiso M, Du Y, Qi L, Huang Y, Hütt-Cabezas M, Warren KE, Le Dret L, Meltzer PS, Mao H, Quezado M, van Vuurden DG, Abraham J, Fouladi M, Svalina MN, Wang N, Hawkins C, Nazarian J, Alonso MM, Raabe EH, Hulleman E, Spellman PT, Li XN, Keller C, Pal R, Grill J, Monje M. Nat Med. 2015 May 4. [Epub ahead of print]
 FDA approves Farydak for treatment of multiple myeloma. U.S. Food and Drug Administration (FDA), February 23, 2015.
Monje Lab (Stanford University School of Medicine, Palo Alto, CA)
Charles Keller (Children’s Cancer Therapy Development Institute, Ft. Collins, CO)
NIH Support: National Institute of Neurological Disorders and Stroke