Repurposing antidepressant may target new medulloblastoma pathway

New research has reported on a novel molecular pathway that causes an aggressive form of medulloblastoma, and it suggests repurposing an antidepressant medication to target the new pathway. This may help combat one of the most common brain cancers in children.

The international, multi-institutional group, led by scientists at Cancer and Blood Diseases Institute (CBDI) at Cincinnati Children's Hospital Medical Center in Ohio, published their results in Nature Medicine (2014; doi:10.1038/nm.3666). The researchers suggest their 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, a part of 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."

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

The scientists used rolipram, an antidepressant approved in Europe and Japan for use as part of behavioral therapy, 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 the cAMP molecule, which restored the GNAS-Gsa pathway's tumor suppression function. This caused the tumors to shrink and subside. The study also suggests that elevating cAMP levels in cells enhances the potency of Sonic hedgehog inhibitors, currently being tested in clinical trials to fight tumor growth.

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 caution 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.

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