Antidepressant identified as potential brain tumor suppressor
An international research team, led by Qing Richard Lu, PhD, scientific director of the Brain Tumor Center at Cincinnati Children’s, has discovered a novel tumor suppressor gene that could help overcoming rapid drug resistance when treating pediatric brain cancer.
The latest findings specifically address aggressive Sonic hedgehog (SHH)-driven medulloblastomas. However, the work may have wider impact. The team showed that Rolipram, a cellular cAMP-elevating agent and antidepressant approved for use in Europe and Japan, effectively inhibits tumor cell proliferation and progression in mice.
Findings were published in September 2014 in Nature Medicine. The study included collaborators from nine medical centers in four countries.
In healthy people, the GNAS gene encodes the Gs-alpha protein, which initiates a molecular signaling cascade that suppresses tumor growth. Mutations disrupting this pathway can lead to rapid cancer cell growth. Lu and colleagues discovered the gene’s role while employing a genome-wide screen to analyze childhood brain tumor samples.
In a line of mice bred to lack the GNAS gene, medulloblastomas shrank when given Rolipram. The researchers believe the drug restores the Gs-alpha pathway’s tumor suppressing power by elevating levels of the signaling molecule cAMP.
“Many chemotherapies become ineffective as soon as the surface receptors they target change, but this drug may help to get inside the cells by targeting a signaling juncture downstream to overcome the drug resistance,” Lu says.
Rolipram is only one drug affecting one part of the Gs-alpha signaling pathway. Lu and colleagues are working to identify other genes and related markers along the pathway. It may be that other drugs acting at other points will prove to be even more effective.
