Paxalisib/Abemaciclib Combination Therapy to Treat AT/RT
Mentor Name: Jeffery Rubens
Atypical teratoid/rhabdoid tumors are the most common malignant brain tumors of infancy. Despite intensive multi-modality therapies, 4-year event free survival remains just 37%. While precision therapies have helped improve the outcomes for many cancers, their development has been limited for the treatment of AT/RT. We have previously identified broad and intense activation of mTORC1 and mTORC2 extending over all molecular subgroups of AT/RT. Paxalisib is a highly brain penetrant, PI3K inhibitor, which simultaneously inhibits activation of mTORC1 and mTORC2. Paxalisib is in clinical trials in adult patients with glioblastoma and pediatric patients with DIPG. We find that Paxalisib is well tolerated in orthotopic mouse models of AT/RT, slows tumor growth, and significantly extends median survival. However, mice ultimately die from recurrent tumors, prompting the need to develop novel combination therapies for a more durable treatment response. We performed RNASeq after dual mTORC1/2 inhibition to identify rational treatment partners to combine with Paxalisib therapy. KEGG pathway analysis identified regulation of the cell cycle as one of the most significantly disrupted pathways with notable decreases in the expression of cyclin family of genes but no significant impact on CDK4 or CDK6 expression. Abemaciclib is a potent CDK4/6 inhibitor, which readily crosses the blood brain barrier, and is currently tested in pediatric clinical trials. Our preliminary data identifies extensive synergies between Paxalisib and Abemaciclib to inhibit phosphorylation of RB, induce cell cycle arrest, and reduce AT/RT cell growth and viability. We hypothesize that these complementary mechanisms of action will allow Paxalisib and Abemaciclib to combine synergistically to significantly extend survival in orthotopic mouse models of AT/RT. We will utilize our extensive collection of patient derived xenografts and cell models to develop orthotopic mouse models representative of each molecular subgroup of AT/RT. We will perform survival studies, bioluminescent imaging, pharmacodynamics, and toxicity profiling to fully characterize the in vivo effects of combination therapy on AT/RT growth and survival.
