The drug restricted the tumor’s growth in a lab dish and improved the survival time of mice that had the tumor implanted into their brains, according to researchers at the Stanford University School of Medicine, in collaboration with colleagues at other institutions. The work is noteworthy because the disease, a brain stem cancer called diffuse intrinsic pontine glioma, is nearly always fatal and lacks an effective treatment.
“There have been over 200 clinical trials of chemotherapy drugs for DIPG, and none have shown any survival benefit,” said Michelle Monje, MD, PhD, assistant professor of neurology at Stanford and a senior author of the paper. “But those trials were conducted before we knew anything about the unique biology of this tumor.”
While the preclinical data in the new study are encouraging, Monje cautioned that the drug, panobionstat, needs further testing in a closely monitored human clinical trial. The research team is now planning such a trial in children with DIPG. Panobinostat was recently approved by the Food and Drug Administration for treatment of a form of blood cancer.
The drug repairs a portion of the cellular machinery now known to be defective in DIPG tumor cells, the new research showed. “A key thing that is wrong with DIPG cancer cells gets corrected by panobinostat,” said Monje, who also treats DIPG patients in her role as a pediatric neuro-oncologist at Lucile Packard Children’s Hospital Stanford. However, the new data also showed that some DIPG cells develop resistance to the drug, which means it will likely need to be combined with other drugs to achieve the best results in humans. “I don’t think this is a cure, but I do think it will help,” she said.
DIPG affects 200-400 school-aged children in the United States each year and has a five-year survival rate of less than 1 percent; half of patients die within nine months of diagnosis. Radiation gives only a temporary reprieve from the tumor’s growth. In addition, it is inoperable: It grows through the brain stem, where breathing and heartbeat are controlled, “with the healthy and diseased cells tangled like two colors of wool knitted together,” Monje said.
The tumor has also been difficult to study. Because it is not surgically removed nor is it typically biopsied, for decades researchers lacked DIPG tissue to examine in a lab. That changed about six years ago, when Monje and other scientists began asking patients’ families to consider donating tumors for research after patients’ deaths. As a result, in 2009, a study led by Monje was the first in the world to report establishment of a line of DIPG cells that could be studied in a dish. Recently, researchers have determined that 80 percent of DIPG tumors have a mutation in histone 3, one of the proteins that packages DNA. The mutation damages the regulation of DNA in cells involved in the cancer — a form of epigenetic change.
In the new study, the research team screened 16 DIPG cell lines derived from patients’ tumors against 83 possible chemotherapy drugs, exposing cells to small samples of each drug. The drugs were chosen because they were thought to have possible effects against brain tumors and were already used in humans or were being developed for human use.
Of the 83 drugs, only a small number showed promise in slowing tumor cells’ growth. The team tracked six of the drugs’ dose-response relationship on DIPG cells and selected panobinostat for further study. They then confirmed the potency and mechanism of panobinostat against DIPG and showed that it normalized some of the detrimental epigenetic changes in the cells and also decreased the expression of genes associated with cancer cell growth.
The team further demonstrated that, in mice that had DIPG tumors implanted in their brain stems, infusing panobinostat directly into the brain stem slowed tumor growth. They also gave the drug systemically by injecting it into mice with DIPG tumors, and showed that enough panobinostat reached the brain stem to prolong the animals’ survival.
In a dish, DIPG cells that survived initial doses of panobinostat developed some resistance to the drug, the study found. However, the team also found that a chemical called GSKJ4, which had previously been shown to inhibit DIPG cells, worked synergistically with panobinostat, with the two agents counteracting known mechanisms of epigenetic dysfunction in the DIPG cells. Although GSKJ4 is not approved as a drug, the finding raises the possibility of developing combinations of drugs to treat DIPG.
“Clearly, the next step is to find out what we can safely combine with panobinostat to increase its efficacy,” Monje said. In addition to the planned clinical trial, which will test whether panobinostat alone improves survival time in children with DIPG, her team will also screen other drugs in combination with panobinostat. “The goal is multimodal treatment to improve outcomes for children with DIPG,” she said.