Addition of altitude sickness drug to chemotherapy shows potential in certain glioblastomas

The combination of a common altitude sickness drug to chemotherapy may benefit patients with certain patients with certain types of glioblastoma, according to study results published in Science Translational Medicine.

The addition of acetazolamide to temozolomide increased sensitivity to treatment and extended survival among mice with gliomas. Accrual now is underway for a first-in-human trial at several Chicago-area institutions.

“The general idea of our project is a repurposing strategy using an agent that has been around for decades and is known to be safe,” Bahktiar Yamini, MD, professor in the section of neurosurgery at The University of Chicago Medicine, told HemOnc Today. “We are repurposing the agent for a combination treatment in brain tumors.”

HemOnc Today spoke with Yamini about the prevalence of temozolomide resistance among individuals with gliomas, the need for new and more effective therapies, why the addition of acetazolamide to temozolomide could be beneficial, and when results of the trial may be available.

Question: What is the prevalence of temozolomide resistance among patients with gliomas?

Answer: Between 50% and 60% of patients with glioblastoma are resistant to temozolomide. However, there are different mechanisms of resistance. One mechanism is an enzyme known as MGMT. People who have high levels of MGMT are very resistant to temozolomide. However, even among patients with low MGMT levels, other mechanisms can promote resistance.

Q: Can you describe the need for new and more effective therapies?

A: There is a significant need. A lot of therapies are administered systemically either via IV or orally and they do not get into the brain because of the blood-brain barrier. Temozolomide only adds months in terms of survival. Although newer therapies might not help all patients, there are subgroups of patients with specific genetics that potentially can be treated with a more individualized approach.

Q: What is the rationale behind adding acetazolamide to temozolomide?

A: This rationale came out of my lab. We were studying temozolomide and its resistance and were looking at the molecule BCL3. We found that, when temozolomide is administered to tumors with high levels of BCL3, levels of an enzyme known as carbonic anhydrase increase. Although this enzyme reduces the efficacy of temozolomide, it can be inhibited by acetazolamide, a drug that is FDA approved for a number of common medical conditions.

Q: Can you summarize the efficacy observed so far in animal models?

A: We gave mice with gliomas temozolomide plus acetazolamide for about 10 days. Although the animals were slightly better than without the addition of the acetazolamide, improvements were not significant. However, we found that carbonic anhydrase stays elevated for many days after temozolomide is administered. In the next experiment, we gave acetazolamide for 21 days and the animals did significantly better than without acetazolamide. We tested this in five or six animal models and, in some models, the animals survived for an extended period, almost as if they were cured. Of note, there were some tumors that did not respond to the combination. There needs to be a certain genetic profile of the tumor to get a positive response.

Q: Are there any concerns about safety?

A: Acetazolamide has been around for a long time and has been used as a diuretic, as an anti-seizure drug, for glaucoma, and probably most famously for altitude sickness. It is a very safe drug. I take it for altitude sickness and have never had a problem. There are rare adverse events that can occur, but probably the most common side effect is a metal taste when drinking carbonated beverages. For this population of patients with gliomas, we want to ensure that, when combining an agent with a chemotherapeutic, that there are no adverse events.

Regardless of the safety of acetazolamide on its own, we need to prove that the combination of acetazolamide and temozolomide is safe in humans. This is what our first-in-human trial will be about.

Q: What is the status of the first-in-human trial?

A: The phase 1 clinical trial is now open at three institutions in the Chicago area. These include North Shore Health System in Evanston, one center in Decatur, Illinois, and another in Peoria, Illinois. There are five more sites in the works, including Rush University Medical Center, The University of Chicago, Northwestern University, Central DuPage Hospital and University of Illinois at Chicago.

Q: H ow will the trial be designed?

A: The trial aims to assess the addition of acetazolamide to standard temozolomide. The primary outcome is safety. Temozolomide is normally given in two phases. In the first phase, temozolomide is given with radiation. During the second phase temozolomide is given alone orally for the first 5 days of each month for a minimum of 6 months. Patients enrolled in the trial will be treated with this standard regimen, and acetazolamide will be added during the second phase. During each treatment cycle, patients will receive acetazolamide for 3 weeks in the form of a pill, taken once in the morning and once at night. We hope to enroll 24 patients — specifically those who have tumors with low levels of MGMT. These patients have some baseline response to temozolomide, and we are trying to get them to respond even better by adding acetazolamide. We hope to complete patient enrollment within 1 year and to start seeing the first results after 6 months.

Q: Is there anything else that you would like to mention ?

A: This trial is sponsored by the nonprofit organization BrainUp. The founders of the organization had a daughter who died of a glioblastoma. It is a grassroots organization that raises money through various fundraising efforts, such as run/walks. Its goal is to bring together institutions in the Chicago area to improve outcomes in glioblastoma. – by Jennifer Southall

Reference:

Wu L, et al. Sci Transl Med. 2018;doi:10.1126/scitranslmed.aar2238.

For more information:

Bahktiar Yamini, MD, can be reached at The University of Chicago Medicine, 5721 S. Maryland Ave., Chicago, IL 60637; email: byamini@surgery.bsd.uchicago.edu.

Disclosure: Yamini reports no relevant financial disclosures.