HDAC/PI3K inhibitors could treat common childhood cancer

The success rate of treating medulloblastoma, the most aggressive form of pediatric cancer, has lagged behind that of treating other childhood cancers. Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) announced Monday that a combo including the HDAC inhibitor panobinostat showed promise in treating mice with medulloblastoma.

Medulloblastoma is the most common malignant brain tumor in children, with 400 children diagnosed in the U.S. each year. The researchers zeroed in on patients with Group 3 medulloblastoma, who have a 40% long-term survival rate, compared with the 80% survival rate of patients with other forms. They targeted the MYC oncogene, which is overexpressed in most Group 3 medulloblastomas, with histone deacetylase inhibitors (HDACIs) and phosphatidylinositol 3-kinase inhibitors (PI3KIs).

Yanxin Pei, assistant professor at Children's National Medical Center, Washington, DC

In mice with Group 3 medulloblastoma, the cocktail was able to kill mouse and human medulloblastoma cells without harming normal cells. While the team found several HDAC inhibitors that killed MYC-activated cancer cells, it highlighted panobinostat as the most potent, said Yanxin Pei, an assistant professor at Children's National Medical Center and co-first author of the study, in the statement. The FDA approved panobinostat, which Novartis ($NVS) markets as Farydak, for multiple myeloma in February last year. And though it's in clinical trials for other cancers, the compound has yet to be tested in medulloblastoma, Pei said.

"Additional studies revealed that panobinostat works by promoting the activity of FOXO1, a gene that interferes with the MYC oncogene," said Kun-Wei (Ken) Liu, co-lead author, in the statement. "We figured that panobinostat and a PI3KI--also known to activate FOXO1--might synergize to block cancer cell survival."

While the Farydak-and-PI3KI combo improved the mice's survival better than either drug on its own, clinical trials could be far off. Because of the limited number of patients and the variability of the disease, clinical trials for the cancer are challenging, said Robert Wechsler-Reya, director of the Tumor Initiation and Maintenance Program at SBP and senior author, in the statement.

"If we can tailor therapies based on the genetic makeup of the tumor--a strategy commonly referred to as personalized medicine--this could have an enormous impact on patients with this disease," Wechsler-Reya said.

- here's the release
- and here's the study abstract