Existing Drug May Help to Treat Aggressive Brain Cancer

An aggressive brain cancer, glioblastoma, progresses very rapidly and often becomes resistant to treatment. Temozolomide (TMZ), the commonest chemotherapy drug used to treat glioblastoma, tends not to be as effective.

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Temozolomide functions by modifying DNA, so that certain proteins that allow the tumors to grow and expand do not express. Unfortunately, some tumor cells are able to resist action of TMZ.

This means that the drug’s effectiveness is often limited, which affects the survival rates of patient.

However, researchers from the University of Chicago in Illinois has made an interesting discovery in a new study.

Acetazolamide, with brand name Diamox, which is a drug commonly used to treat altitude sickness and other health problems, such as glaucoma and even seizures, may counter the resistance put up by glioblastoma cells, thereby increasing the effect of TMZ.

Study director Dr. Bahktiar Yamini explains that, if the new findings hold strong, acetazolamide would be a very convenient therapeutic aid, since it is “cheap to make, easy to take, and has limited side effects.”

The researchers’ results have now been published in the journal Science Translational Medicine

The researchers discovered that patients with this aggressive form of brain cancer appeared to be resistant to TMZ treatment if they had high levels of B cell CLL/lymphoma 3 (BCL-3), a protein able to thwart the action of the chemotherapy drug.

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BCL-3 blocks TMZ by activating an enzyme that protects the tumor cells called k, and allows them to continue their cycle.

The researchers experimented with acetazolamide, working with a mouse model of glioblastoma, testing to see whether it, would block the activity of carbonic anhydrase, thereby allowing TMZ to perform its work.

“We tested this combination treatment strategy in several animal models,” explains Dr. Yamini.

This strategy, the researchers found, cured some of the mice, while other animals saw a 30–40 percent increase in survival time following the combination treatment.

That is because acetazolamide is a carbonic anhydrase inhibitor, and the team was able to measure this by first looking at existing studies covering human patients with glioblastoma.

Dr. Yamini and team found in their preliminary research that individuals with lower BCL-3 levels also had longer survival rates after treatment with TMZ, compared with other patients with high levels of this protein.

“An important feature of predictors like BCL-3 is that they are informative,” explain the researchers. “They can identify pathways to improve treatment response.”

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The scientists were eventually able to pinpoint acetazolamide as a carbonic anhydrase inhibitor that could support the effect of TMZ by looking at BCL-3 mechanisms.

“Our data,” add the authors, show that it is the “induction of [carbonic anhydrase II] by TMZ that is important in modulating response to therapy.”

Dr. Yamini and colleagues suggest that in future, a prospective randomized clinical trial should be conducted in order to confirm that testing for BCL-3 can indicate which patients will respond best to TMZ, and which are likely to be treatment resistant.

The researchers hope that a combination of TMZ and acetazolamide could in the long run be used to increase treatment efficacy for patients with high levels of BCL-3.

 

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