Early Study Identifies Tumor-Suppressor Gene, Potential Therapy for Medulloblastoma


Key Points

  • In a lab study, researchers identified GNAS as a potent tumor-suppressor gene in Sonic hedgehog–driven medulloblastoma.
  • Treating mice with the antidepressant rolipram resulted in elevated levels of cAMP, which restored the GNAS-Gsa pathway’s tumor-suppression function.
  • More research is needed before these results could become directly relevant to clinical treatment.

An international, multi-institutional research group led by scientists at the Cancer and Blood Diseases Institute (CBDI) at Cincinnati Children’s Hospital Medical Center has identified a novel molecular pathway that causes an aggressive form of medulloblastoma, The study, reported by He et al in Nature Medicine, suggests that repurposing an antidepressant medication to target the new pathway may help combat one of the most common brain cancers in children.

According to the researchers, these laboratory findings in mouse models of the disease could lead to a more targeted and effective molecular therapy that would also reduce the harmful side effects of current treatments, which include chemotherapy, radiation, or surgery.

“Although current treatments improve survival rates, patients suffer severe side effects and relapse tumors carry mutations that resist treatment,” said lead investigator Q. Richard Lu, PhD, Scientific Director of the Brain Tumor Center, part of the CBDI at Cincinnati Children’s. “This underscores an urgent need for alternative targeted therapies, and we have identified a potent tumor suppressor that could help a subset of patients with an aggressive form of medulloblastoma.”

Study Details

Using genetically-engineered mice to model human medulloblastoma, the authors identified a gene called GNAS that encodes a protein called Gsa. Gsa kicks off a signaling cascade that researchers found suppresses the initiation of an aggressive form of medulloblastoma driven by a protein called Sonic hedgehog—considered one of the most important molecules in tissue formation and development.

The scientists used an antidepressant medication called rolipram, which is currently approved for behavioral therapy for use in Europe and Japan, to treat mice that were engineered not to express the GNAS gene. Lack of GNAS allowed aggressive formation of medulloblastoma tumors in neural progenitor cells of the GNAS-mutant mice.

Rolipram treatment in the mice elevated levels of a molecule called cAMP, which restored the GNAS-Gsa pathway’s tumor-suppression function, causing the tumors to shrink and subside. The study also suggested that elevating cAMP levels in cells enhances the potency of Sonic hedgehog inhibitors, currently being tested in clinical trials to fight tumor growth.

Early Results

The scientists stressed that a significant amount of additional research is needed before their findings could become directly relevant to clinical treatment. The authors also cautioned that the effect of raising cAMP levels may depend on the type of cancer, and that laboratory results in mice do not always translate uniformly to humans.

Dr. Lu is the corresponding author for the Nature Medicine article.

The study was funded in part by the National Institutes of Health and the Candian Institutes of Health Research. The study authors reported no potential conflicts of interest.

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