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Gene Suppressor Therapy Could Improve Survival for Mesothelioma Patients

Published: February 24, 2023

New mesothelioma research is being performed at The Netherlands Cancer Institute. The researchers are looking at new combinations of medications to be used on patients that have mesothelioma with BAP1 genetic mutations. More than half of patients with mesothelioma have changes in the BAP1 tumor suppressor gene. When the BAP1 gene is altered, it allows more treatments to be effective because there are vulnerabilities not found in non BAP1 patients. The treatment created a four-week improvement in survival. The combination, zoledronic acid and tazemetostat, have only been used in single cells and animal models. The research showed that there is a reduction of mesothelioma cells in mice when treated with the drugs. Mesothelioma is traditionally a hard cancer to treat. Chemotherapy and immunotherapy can only do so much in extending survival. Targeting gene mutations with different drugs could be a more effective solution. If the combination does well in clinical trials, there is a chance it could be used in people with mesothelioma.

The drug combination was tested on mice with mesothelioma to determine effectiveness. Mice either received tazemetostat, zoledronic acid, or a combination of both. To determine effectiveness, researchers monitored tumor volume over the time of treatment. Researchers found that the drug combination showed significant inhibition of growth in tumors. It was also observed that the drugs worked better on BAP-1 deficient tumors. After the mice model, researchers tested the combination on a different animal model using mice that is more like human cancers. They were observed until they showed respiratory distress and weight loss. When treated with both the zoledronic acid and tazemetostat, the survival was prolonged to a total of 95 days. The control group had a median survival of 70 days. When the mice were treated with just one drug, they did not have an increase in survival. When given 250 mg/kg tazemetostat twice a day, the median survival was 72 days. When given .2 mg/kg zoledronic acid once a day, the median survival was 74 days. The mice in the control groups did not have any body weight changes. This could allow higher doses in further clinical trials of the drugs.

Researchers at the Netherlands Cancer Institute believe the combination therapy could be a good option for mesothelioma. This could lead to better treatments and better survival times in mesothelioma patients. Grouping patients based on dependent biomarkers could help create new ways of treating patients with mesothelioma and could lead to better outcomes for patients. Tazemetostat has been approved for certain solid cancers and non-Hodgkin lymphoma. A study in May 2022 tested the drug on 70 BAP1 cancer patients. Survival improved to 41 weeks. It is also promising that less than five percent of the patients had severe effects from the drugs. Patients in the trial had a disease control rate of 54.1 percent at 12 weeks and 32.8 percent at 24 weeks. All patients in the study were receiving treatment as a second line therapy, which means they tried other cancer treatments that ultimately failed. Tazemetostat works by blocking the enzyme EZH2. The enzyme inhibits the genes that slow down cancer. Patients with BAP1 have more EZH2, making their mesothelioma more aggressive than others.

Guarav Kumar Pandey et al., “Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma” Cell reports Medicine (January 18, 2023). [Link]
Marjorie G. Zauderer M.D. et al., “EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study” The Lancet Oncology (May 16, 2022). [Link]
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