Altitude Sickness Drug May Help Glioblastoma Patients

JULY 24, 2018
Einav Keet
Researchers from the University of Chicago Medicine have found that a drug used to relieve altitude sickness may help slow the progression of glioblastoma, an aggressive form of brain cancer.

A glioblastoma is a fast-growing form of brain cancer, and the most common primary malignant brain tumor, making up 16% of all primary brain and central nervous system neoplasms. In the United States, the incidence rate of glioblastoma is 3.19 per 100,000 persons, with a median age of 64 years, and is slightly more common in men than in women. Symptoms can include an increase in intracranial pressure, headache, and focal or progressive neurologic deficits, and as many as one-quarter of patients report seizure as a presenting symptom. The survival rate for patients with glioblastoma is low—only 2.5 years—and fewer than 5% of patients survive to 5 years after diagnosis.

Surgery on glioblastomas is difficult to perform due to the tumor’s invasive nature into areas of the brain that control speech, motor function, and the senses. Treatment for the condition includes radiation along with the oral chemotherapy drug temozolomide, which kills tumor cells by damaging DNA.

In a new study recently published in the journal Translational Science, researchers note that in some patients, tumor cells are able to block or repair the damage caused by temozolomide, rendering the drug ineffective against glioblastoma. The researchers found that patients who were unresponsive to temozolomide treatment had elevated levels of a protein called B cell CLL/lymphoma 3 (BCL-3), which acts to block cancer cells from the drug by activating carbonic anhydrase II, a protective enzyme. The altitude sickness drug acetazolamide—also used in patients with glaucoma, epilepsy, heart failure, and seizures—is a carbonic anhydrase inhibitor, and the researchers investigated its use in combination with temozolomide against glioblastoma.

The research team injected mice with high BCL-3-expressing human gliomas and found that acetazolamide increased tumors’ sensitivity to temozolomide, allowing the chemotherapy drug to effectively kill the tumor cells. "We tested this combination treatment strategy in several animal models," said study director Bahktiar Yamini, MD, in a recent statement. He notes that some were cured, while others had a 30% to 40% increase in their survival time. Dr Yamini and his colleagues also examined previous human studies, finding that patients with lower BCL-3 survived longer when treated with temozolomide than patients with higher levels.

“Our data suggest that BCL-3 might be a useful indicator of glioma response to alkylating chemotherapy and that acetazolamide might be repurposed as a chemosensitizer for treating TMZ-resistant gliomas,”  the authors write. They postulate that the combination of acetazolamide along with temozolomide might be particularly effective in those glioblastoma patients who have a high BCL-3 expression, but that a prospective randomized clinical trial will be needed to validate the use of BCL-3 to predict which patients will benefit from the use of temozolomide. The team says they will soon be recruiting patients into a Chicago-area trial spanning several institutions.

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