Abstract 5226: The PI3K inhibitor Paxalisib combines synergistically with the pan-Raf inhibitor TAK580 (DAY 101) to extend survival in orthotopic xenograft models of atypical teratoid/rhabdoid tumors

Abstract

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive pediatric brain tumors and the most common malignant brain tumors of infancy. The four-year event-free survival rate is only 37%. For patients with relapsed AT/RT, there are limited treatment options, but novel precision therapies may help improve survival for patients with this deadly disease. We have previously identified strong activation of the PI3K-AKT-mTOR (mTOR) signaling pathways in AT/RT. Paxalisib is a highly brain-penetrant PI3K inhibitor acting upstream of mTOR. We find that Paxalisib slows tumor growth in orthotopic xenograft models of AT/RT and extends median survival from 40 to 54 days (p=0.001, log-rank test). RNASeq after mTOR pathway inhibition identifies reflexive activation of the MAPK pathway as a possible mechanism of therapy resistance (KEGG pathway analysis). TAK580 (DAY 101) is a highly brain penetrant, pan-RAF kinase inhibitor, currently in clinical trials in pediatric low grade gliomas (NCT03429803, NCT04775485). Paxalisib combines synergistically with TAK580 to reduce AT/RT growth and viability (Bliss synergy score 24.22). A pilot study suggests combination therapy is well tolerated in mice bearing AT/RT orthotopic xenografts and slows tumor growth compared to Paxalisib alone and vehicle controls. This novel combination of precision therapies can translate into a clinical trial aimed at improving survival in this deadly disease. Citation Format: Kristen Malebranche, Tyler Findlay, Charles Eberhart, Eric Raabe, Jeffrey Rubens. The PI3K inhibitor Paxalisib combines synergistically with the pan-Raf inhibitor TAK580 (DAY 101) to extend survival in orthotopic xenograft models 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 5226.