Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas
Pooja Panwalkar, Benita Tamrazi, Derek Dang, Chan Chung, Stefan R. Sweha, Siva Kumar Natarajan, Matthew Pun, Jill Bayliss, Martin P. Ogrodzinski, Drew Pratt, Brendan Mullan, Debra Hawes, Fusheng Yang, Chao Lü, Benjamin R. Sabari, Abhinav Achreja, Jin Heon, Olamide Animasahun, Marcin Cieślik, Christopher Dunham, Stephen Yip, Juliette Hukin, Joanna J. Phillips, Miriam Bornhorst, Andrea M. Griesinger, Andrew M. Donson, Nicholas K. Foreman, Hugh Garton, Jason Heth, Karin M. Muraszko, Javad Nazarian, Carl Koschmann, Li Jiang, Mariella G. Filbin, Deepak Nagrath, Marcel Kool, Andrey Korshunov, Stefan M. Pfister, Richard J. Gilbertson, C. David Allis, Arul M. Chinnaiyan, Sophia Y. Lunt, Stefan Blüml, Alexander R. Judkins, Sriram Venneti
Abstract
, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.