COPD Drug Could be Repurposed for Brain Tumor Treatment

Roflumilast normally treats inflammatory lung diseases, but was found to dramatically inhibit tumor growth.

Roflumilast normally treats inflammatory lung diseases, but was found to dramatically inhibit tumor growth.

Scientists may have found a new way to combat a common childhood brain tumor that has become resistant to other medications, according to Stanford University researchers. The drug, Roflumilast, proved effective in the treatment of brain tumors in mouse models that were resistant to the drug Vismodegib.

Roflumilast is normally used to treat inflammatory lung diseases, but was found to dramatically inhibit tumor growth from the start of the study. It is already FDA-approved and available to patients, but the side effects are of much concern to patients and physicians prescribing the medication.

“New drugs beyond Vismodegib are needed because the current treatments for medulloblastoma have severe side effects, cure only about two-thirds of patients, and leave treated patients with lasting damage,” said Dr. Xeucai Ge, the first author of the study.

Some birth defects and tumors are caused by defects in the way cells communicate with one another in the embryo during development. The Hedgehog signaling pathway is a cell-to-cell communication system essential for the normal growth of many tissues and organs in animal embryos.

The Hedgehog signaling proteins have many roles, including stimulating the proliferation of certain types of precursor cells before they mature into neurons in the developing cerebellum. When mutations damage the genes that encode components of the Hedgehod signaling system, cells may get confused that they are receiving a growth-stimulating signal, when in actuality they are not.

This leads to loss of growth control and contributes to a wide range of tumors including medulloblastoma, the most common malignant brain tumor in children. Basal cell carcinoma of the skin is also caused by this loss of growth control and is treatable with Vismodegib.

However, basal cell carcinoma of the skin can develop further mutations, like in brain tumors, and can lead to resistance of Vismodegib. Cancer cells mutate continuously within medulloblastomas so even cancers that initially respond to treatment with Vismodegib run the risk of losing that response with mutated resistant cells taking over.

Vismodegib targets a specific signal in the Hedgehog signaling pathway that inhibits cell division. The current study reveals a new way in which the response to a Hedgehog signal is regulated. This could provide a new target for treatment.

Scientists found that the Semaphorin 3 protein enhances the response to a Hedgehog signal. Elevated levels of the protein are found in medulloblastomas and scientists hypothesize that blocking the effect of Semaphorin 3 could inhibit the response to Hedgehog and therefore cell division.

Semaphorin 3 activates the enzyme called PDE4D. By using Roflumilast to inhibit PDE4D, scientists were able to block tumor growth from the loss of control of Hedgehog signaling. Since Roflumilast affects a process that is independent of the one affected by Vismodegib, it works against Vismodegib-resistant tumors.

Roflumilast is already used to treat COPD. This drug, as well as other PDE4D inhibitors, are currently being tested in clinical trials to improve cognitive and psychological disorders, including memory loss.

However, the drugs have severe side effects, including weight loss and depression. PDE4D inhibitors could also be effective for treating more common cancers such as basal cell carcinoma which also arises as a result of damage to Hedgehog signaling.

“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,” said Dr. Ge.