ATRT-26. The PI3k inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors

We previously identified high activation of mTORC1 and mTORC2 in AT/RT by immunohistochemistry of 18 primary tumors expanding over each molecular subgroup of AT/RT. Paxalisib is a highly brain-penetrant PI3k inhibitor acting upstream of mTORC1/2 to fully inhibit the activation of both complexes. Ongoing pediatric clinical trials have reported Paxalisib as safe and well-tolerated. We find that Paxalisib leads to minimal toxicities in mice bearing AT/RT orthotopic xenografts, slows tumor growth (as determined by bioluminescent imaging), and significantly extends survival (CHLA-06: 40 to 54 days, p=0.0011; BT12: 21 to 35 days, p=0.02). However, due to limited durability of single agent therapy, we conducted pilot studies to identify rational combination therapies to further enhance these survival benefits. RG2833 is a novel, highly brain penetrant, histone deacetylase 1/3 (HDAC1/3) inhibitor. HDAC inhibitors have previously been identified as synergistic partners with PI3k/mTOR inhibitors through complementary activation of FOXO signaling pathways. We hypothesized that RG2833 would synergize with Paxalisib, minimize toxicities compared with pan-HDAC inhibitors, and maximize therapeutic benefits due to superior CNS penetration. We demonstrate that Paxalisib and RG2833 combine synergistically to decrease AT/RT cell growth (SynergyFinder ZIP score 11.1; CellTiter-Blue Cell Viability Assay, p<0.0001), and increase apoptosis (Western blot cPARP, MUSE Annexin V Assay, ANOVA p<0.001) compared to each agent alone and DMSO control. Our pilot combination study in orthotopic xenograft models of AT/RT demonstrate that combination therapy is well tolerated and slows tumor growth more significantly than each agent alone and vehicle control (IVIS bioluminescent imaging). This novel combination therapy could readily translate into a new clinical trial aimed at improving survival in this deadly pediatric brain tumor.