TMOD-30. R206H ACVR1 SIGNIFICANTLY ACCELERATES DIFFUSE INTRINSIC PONTINE GLIOMA PATHOGENESIS

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) comprise 15% of pediatric brain tumors and are the leading cause of death for children with brain tumors. In spite of numerous clinical trials, little progress has been made in prolonging the survival of DIPG patients. As there are currently no effective treatments, it is important to develop mouse models in order to understand the biology of these tumors. Recently we, and others have discovered activating bone morphogenic protein (BMP) pathway mutations in ACVR1, which encodes for the Activin A receptor (ALK-2). ACVR1 mutations are found in 25% of DIPG patients and commonly co-occur with the H3.1 K27M mutation. In order to study how these two mutations co-operate and affect tumor biology, our lab has developed the first genetically engineered mouse model (GEMM) driven by both mutations through the use of the RCAS/t-va retroviral system. Preliminary results show that brainstem progenitor cells grown as neurospheres and infected with R206H-ACVR1 virus had increased pSMAD1/5/8 and Id1 expression in vitro, indicating increased BMP signaling. In vivo, infection of brainstem progenitors in nestin tv-a (Ntv-a); p53 floxed (p53fl) mice with R206H-ACVR1, H3.1 K27M, PDGFA, and Cre had significantly decreased survival relative to mice infected with WT ACVR1, WT H3.1, PDGFA, and Cre, or H3.1K27M; PDGF-A; and Cre suggesting that the BMP pathway is pro-tumorigenic. Additionally the combination of ACVR1 R206H and H3.1 K27M enhanced angiogenesis as evidenced by CD31 staining and western blot, providing a possible mechanism of co-operation. Finally, PDGF-A; ACVR1 R206H; H3.1 K27M; p53-deficient tumor derived neurospheres were tested in vitro with the ACVR1 inhibitor LDN 212854 and were found to have significantly decreased proliferation and survival. Based on these results, LDN 212854 is currently being evaluated in vivo in our model with the hopes that it will be a new therapeutic agent for treating DIPG.