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Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy with a four-year event-free survival of 37%. Previously, we have identified high activation of both mTORC1 and mTORC2 through immunohistochemistry of 18 primary human AT/RT. The PI3K-Akt-mTOR signaling pathway drives tumorigenicity by promoting cancer cell growth and survival. 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, with minimal dose limiting toxicities. Paxalisib treatment in mice bearing orthotopic xenografts of AT/RT slowed tumor growth and significantly extended survival from 40 to 54 days (bioluminescent imaging, log rank test p=0.0011). However, due to limited durability of single agent therapy, we conducted pilot studies to identify rational combination therapies to enhance Paxalisib survival benefits in AT/RT. RG2833 is a novel, highly brain penetrant, histone deacetylase 1/3 (HDAC1/3) inhibitor. Our preliminary data has shown that Paxalisib and RG2833 combine synergistically to decrease AT/RT cell growth (SynergyFinder ZIP score 11.1; CellTiter-Blue Cell Viability Assay, p Citation Format: Tyler Findlay, Kristen Malebranche, Charles Eberhart, Eric Raabe, Jeffrey Rubens. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5225. |
