(P 360) TREATMENT OF MALIGNANT PERIPHERAL NERVE SHEATH TUMOR WITH BROMODOMAIN EXTRA TERMINAL INHIBITOR (BETI) IN COMBINATION WITH RADIOTHERAPY

Objective: Malignant peripheral nerve sheath tumors (MPNST) harbor mutations in the polycomb repressive complex 2 (PRC2) in 70% of tumors—this loss of PRC2 results in epigenetic changes that decrease histone methylation and increase histone acetylation of histone 3 lysine 27. The increase in histone acetylation is indicative of increased activity of bromodomain and extra-terminal domain (BET) proteins could make the tumors bind more bromodomain proteins, which could be targeted by BET inhibitors (BETi). Given that radiation therapy (RT) is part of the standard treatment regimen offered to MPNST patients, we examined whether pretreatment with BETi could improve response to RT.

Methods: Mice were implanted with patient-derived xenografts (PDX) of PRC2-wildtype models, MPNST007 or MPNST0764. For comparison, mice were implanted with PDX tissues in PRC2-mutant models MPNST3813E or S462. Mice were segregated into vehicle and BETi treatment groups and treated with either vehicle or drug for one week before RT was initiated. Half of the mice in each treatment group received radiation (1 Gy per fraction for 5 days for a total of 5 Gy). The study endpoints were (1) tumor growth rates, (2) tumor size and weight at study termination, (3) immunohistochemical (IHC) staining for biomarkers of proliferation (Ki67), apoptosis (cleaved caspase 3, CC3), and DNA damage (γH2AX).

Results: Tumor regression was observed in both PRC2-mutant PDX and PRC2-wildtype tumors in BETi and RT alone and BETi in combination with RT. There is a corresponding decrease in proliferation (Ki67) in the single agent BETi and RT therapy arms as well as the combination BETi with RT. There is also an increase in the DNA damage (γH2AX) observed in the RT alone and RT in combination with BETi.

Conclusion: Genetic mutations in MPNST tumors result in the sensitivity to BETi treatment in combination with RT. A decrease in tumor growth and improved response to RT is observed in MPNST when pretreated with BETi. These findings suggest that BETi could be incorporated into treatment strategies for MPNST patients for better patient outcomes.