PRECLINICAL EFFICACY OF COMBINED RADIOTHERAPY WITH VENETOCLAX TREATMENT IN TARGETING DIFFUSE MIDLINE GLIOMAS

Abstract BACKGROUND: H3K27M diffuse midline gliomas (DMGs) are highly aggressive pediatric tumors of pons, thalamus or spinal cord. The only standard-of-care for DMGs is radiation therapy (RT) since the anatomical location of such tumors does not allow surgical resection. Tumor response to RT is at best transient as tumor becomes refractory due to radioresistance. Tumor relapse after RT is a major hurdle in treating DMGs. The mechanism of development of radioresistance due to RT-induced stress has not been studied in DMGs yet. METHODS: We performed an integrated genomic analysis to determine genes responsible for radioresistance and a targeted drug screen to identify drugs synergizing with radiation in DMG. Effect of venetoclax on radiation-naïve and 6Gy radiated DMG cells was evaluated by studying cell death and apoptosis. The efficacy of combining venetoclax with radiation was evaluated in vivo using orthotopic xenograft models. RESULTS: We identified that BCL2 as a key regulator of tumor growth in DMGs after radiation. Radiation sensitizes DMGs to venetoclax treatment. While venetoclax as a monotherapy was not cytotoxic to DMG cells, post-radiation venetoclax significantly increased cell death and apoptosis. Combining venetoclax with RT significantly enhanced the survival of mice with DMG tumors in vivo. Further, we found that the mechanism of radiation-induced cytotoxic effect of venetoclax is p53-independent in DMGs. CONCLUSIONS: This study shows that venetoclax impedes the anti-apoptotic function of radiation-induced BCL2 in DMG leading to apoptosis. Our results are encouraging because, in clinical settings, majority of the DMG patients, irrespective of the tumor p53 status, will benefit from combining RT with venetoclax treatment. Since venetoclax either alone or in combination with chemotherapy drugs are currently in clinical trials for other pediatric cancers, a phase 1b trial is imminent for treating DMGs with venetoclax in combination with radiation therapy.