Epilepsy drug breaks defence of brain cancer against chemo

The drug, also used for altitude sickness makes aggressive brain cancer more vulnerable to chemotherapy

A common drug used for altitude sickness, glaucoma and epilepsy has shown promise in treating an aggressive form of brain cancer.

A study published in the journal Science Translational Medicine revealed this new role of the drug acetazolamide in glioblastomas. Sold under the trade name Diamox, is “cheap to make, easy to take and has limited side effects,” said study director Bahktiar Yamini, MD, a professor of neurosurgery at the University of Chicago Medicine. “I take it myself, whenever I go to the Rocky Mountains,” he said, “two pills a day.” The most common side effect of Diamox is “a metallic taste when drinking something carbonated.”

“We tested this combination treatment strategy in several animal models”

The most frequently used chemotherapy for gliomas is a drug called temozolomide (TMZ). However, not all patients respond to this drug. Median survival with this disease is about 14 months. TMZ acts by damaging DNA in ways that can kill tumor cells. But some tumor cells are able to block or repair this type of DNA damage. This limits the drug’s impact.

The researchers found that most glioma patients with high levels of a protein called BCL-3 (B cell CLL/lymphoma 3) were unresponsive to the beneficial effects of TMZ. BCL-3 shields cancer cells from TMZ damage by activating a protective enzyme known as carbonic anhydrase II. Acetazolamide, however, is a carbonic anhydrase inhibitor making the cancer cells vulnerable to the chemotherapy drug once more. It can restore TMZ’s ability to kill tumor cells. Adding acetazolamide to TMZ enabled mice with gliomas to survive longer.

“We tested this combination treatment strategy in several animal models,” Yamini said. It cured some of them. Others had a 30 to 40 percent increase in survival time.

“An important feature of predictors like BCL-3 is that they are informative,” the authors note. “They can identify pathways to improve treatment response.” By examining those pathways, the authors identified carbonic anhydrase inhibitors, such as acetazolamide, as a way to reduce resistance to temozolomide.

Validating the use of BCL-3 to predict which patients will benefit from the use of temozolomide will require verification in a prospective randomized clinical trial, the authors note. They also suggest that repurposing acetazolamide along with temozolamide might be particularly effective in a subgroup of appropriate patients with tumors that have high BCL-3 expression. They have already organized a trial at several Chicago area institutions and hope to recruit patients soon.