Netherlands Cancer Institute Tests New Mesothelioma Therapy

Research for a new type of mesothelioma treatment is underway at the Netherlands Cancer Institute. Scientists are exploring a novel combination of existing medications for patients with BAP1 genetic mutations. 

More than half of all mesothelioma patients show alterations in the BAP1 tumor-suppressor gene. An altered BAP1 gene allows for vulnerabilities that make specific treatments more effective. The combination treatment led to about a four-week increase in median survival.

Researchers have previously only explored the combination of zoledronic acid and tazemetostat in single cells and animal models. This latest research shows promising results in reducing the growth of cancer cells in mice with mesothelioma. 

Asbestos exposure is the primary cause of mesothelioma. Treatment options, such as chemotherapy and immunotherapy, are limited in how long they can extend survival. Targeting gene mutations with a particular combination of drugs could prove more effective. 

“If these drugs also prove to work well in clinical trials, we can offer patients a new and hopefully better treatment option,” said Jitendra Badhai, one of the study authors. 

Drug Combination Improves Survival in Mice

Study investigators treated mice with mesothelioma to determine the effectiveness of the new drug combination. The mice received either tazemetostat, zoledronic acid or a combination of both. The research team then monitored tumor volume over time. 

The results showed that the combination of tazemetostat and ZA resulted in significant growth inhibition. The drugs were much more effective on BAP1-deficient tumors. 

The researchers then tested the treatment in a different animal model. This model more closely resembles human malignancy with aggressive tumor formation. The study team monitored the mice until they showed respiratory distress and significant weight loss. 

The combination treatment of ZA and tazemetostat resulted in a 4-week prolongation of median survival for a total of 95 days. The control survival was 70 days. 

The study authors noted that treatment with single agents provided limited benefits. Tazemetostat at a concentration of 250 mg/kg twice daily led to a median survival of 72 days. ZA at 0.2 mg/kg once daily resulted in a median survival of 74 days.

Monitoring body weight during combination treatment showed no differences compared with control doses. The researchers noted that this result justifies dose-escalation in future mesothelioma clinical trials.

Researchers Are Optimistic

The researchers at the Netherlands Cancer Institute are optimistic about the combination of tazemetostat and ZA. The results from the new study could lead to a better mesothelioma prognosis for more patients. 

“Identifying biomarker-based dependencies and exploiting them have a high potential to lead to new treatment options,” the study authors at the Netherlands Cancer Institute said. “Stratification of patients based on biomarkers could add much needed therapeutic strategies against this highly aggressive disease.”

The U.S. Food and Drug Administration has approved tazemetostat to treat some solid tumors and non-Hodgkin lymphoma. A clinical trial in May 2022 tested the drug on 70 patients with recurrent cancer and the BAP1 mutation. The median overall survival was 41 weeks. Less than 5% of the patients experienced severe drug-related side effects.

During the trial, participants had a disease control rate of 54.1% at 12 weeks and 32.8% at 24 weeks. Patients in the study received the drug in the second-line setting, meaning they had tried and failed previous therapies. 

Tazemetostat blocks the enzyme EZH2. This enzyme inhibits the genes that restrict cancer tumor growth. Patients with BAP1 mutations have a higher expression of EZH2, leading to a more aggressive form of mesothelioma. 

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