Abstract
Researchers have linked decreased expression of GNAS, a key player in many signaling pathways, to an aggressive subtype of medulloblastoma driven by the Sonic hedgehog signaling pathway. The findings suggest that GNAS expression could be used as a prognostic biomarker, or possibly to direct the development of new therapeutics.
In the last few years, cancer researchers have recognized that medulloblastoma, a brain cancer that disproportionately affects children, consists of at least four molecular subtypes. A better understanding of those subtypes may help guide the development of targeted drug therapies and explain why up to 20% of patients experience recurrence after developing resistance to treatment.
Reporting in Nature Medicine, an international team of researchers linked decreased expression of GNAS, which encodes Gαs, a key player in G protein-coupled receptor signaling, to aggressive tumors in the medulloblastoma subtype driven by activation of the Sonic hedgehog (SHH) pathway. In mice, the researchers found that Gαs suppressed tumor growth. In addition, after studying samples of human medulloblastoma tissue from more than 200 patients—from cohorts in Boston, MA, and Heidelberg, Germany—they found that patients with low expression of GNAS had a lower overall survival time than patients with normal GNAS expression.
“Very few pathways have been identified that suppress the Sonic hedgehog types of medulloblastoma, which are very heterogeneous,” says Q. Richard Lu, PhD, the study's senior author and scientific director of the Brain Tumor Center at Cincinnati Children's Hospital Medical Center in Ohio. He says his team's findings suggest GNAS may be a prognostic biomarker for SHH-associated medulloblastoma.
The gene's connection to SHH-driven medulloblastoma may also have therapeutic implications. The researchers reported that Gαs suppresses SHH signaling in medulloblastoma, in part, by activating the cyclic AMP (cAMP)–protein kinase A pathway. Knowing that the phosphodiesterase-4 inhibitor rolipram, which is already approved for human use as an antidepressant in Japan and Europe, raises cAMP levels, Lu and his colleagues treated mice genetically engineered not to express Gnas—and thus to develop medulloblastoma—with the drug. This resulted in smaller tumors and an extension of lifespan.
Pediatric oncologist Will Parsons, MD, PhD, co-director of neuro-oncology at Texas Children's Cancer and Hematology Centers in Houston, says the research suggests a promising approach to treating a complicated cancer.
“The attractive possibility raised in the new study is that targeting Gαs, in combination with other drugs targeting the Sonic hedgehog pathway directly might be a useful strategy,” says Parsons. “Such an approach might have the potential to prevent tumor resistance and be more effective than treating with a single agent alone.”
Lu's research is an “excellent first step, but the harder one will be showing that there's some clinical relevance” to targeting SHH pathway tumors using this strategy, Parsons says.
Lu says he's now planning a clinical trial of the drug in medulloblastoma patients.
