|Stanford's Xuecai Ge|
Close to three years ago the FDA approved Erivedge (vismodegib) to treat basal cell carcinoma, an advanced skin cancer. More recently the drug has been shown to be effective--at least temporarily--against a subtype of a common form of childhood brain tumor, medulloblastoma. A scientific team at Stanford, though, says the brain tumor constantly mutates, eventually becoming resistant to the drug. But using another approved COPD drug, they say they were able to target a new mechanism of action that can effectively fight the drug-resistant tumor.
Erivedge works in the the sonic hedgehog signaling pathway. Once genes involved in hedgehog signaling system are damaged, they can start sending errant growth stimulation signals that spur tumors' growth. Erivedge can stop cell division, at least for awhile, and slow the cancer.
The Stanford group, though, noted that the Semaphorin 3 protein enhances the response to hedgehog signaling, activating the PDE4D enzyme. They used a different drug, Darilesp (roflumilast), to block the enzyme, using the separate mechanism to tackle tumors in drug-resistant mice.
The investigators also note, though, that there's a catch. PDE4D inhibitors are in the clinic for use in guarding against cognition disorders and memory loss, but have also been linked to severe depression and weight gain.
They could also possibly be a new target for basal cell carcinoma drug research.
"Our study shows that it is a priority to repurpose PDE4D inhibitors, perhaps in combination with other medicines, as a promising therapy for devastating and potentially fatal childhood brain tumors," says Dr. Xuecai Ge, the first author of the study, which was published in eLife.