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
| Autor: | Tyler Findlay, Kristen Malebranche, Eric Raabe, Charles Eberhart, Jeffrey Rubens |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Neuro-Oncology. 24:i9-i9 |
| ISSN: | 1523-5866 1522-8517 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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