gsk-j4 and Brain-Stem-Neoplasms

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain cancer whose median survival time is under one year. The possible roles of the two most common DIPG associated cytoplasmic ACVR1 receptor kinase domain mutants, G328V and R206H, are reexamined in the context of new biochemical results regarding their intrinsic relative ATPase activities. At 37 °C, the G328V mutant displays a 1.8-fold increase in intrinsic kinase activity over wild-type, whereas the R206H mutant shows similar activity. The higher G328V mutant intrinsic kinase activity is consistent with the statistically significant longer overall survival times of DIPG patients harboring ACVR1 G328V tumors. Based on the potential cross-talk between ACVR1 and TβRI pathways and known and predicted off-targets of ACVR1 inhibitors, we further validated the inhibition effects of several TβRI inhibitors on ACVR1 wild-type and G328V mutant patient tumor derived DIPG cell lines at 20-50 µM doses. SU-DIPG-IV cells harboring the histone H3.1K27M and activating ACVR1 G328V mutations appeared to be less susceptible to TβRI inhibition than SF8628 cells harboring the H3.3K27M mutation and wild-type ACVR1. Thus, inhibition of hidden oncogenic signaling pathways in DIPG such as TβRI that are not limited to ACVR1 itself may provide alternative entry points for DIPG therapeutics.

Topics: Activin Receptors, Type I; Benzazepines; Brain Stem Neoplasms; Cell Line, Tumor; Diffuse Intrinsic Pontine Glioma; Dose-Response Relationship, Drug; Humans; Imidazoles; Mutation; Panobinostat; Phosphotransferases; Prognosis; Protein Conformation; Pyrimidines; Quinoxalines; Receptor Cross-Talk; Receptors, Transforming Growth Factor beta

Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.

Topics: Animals; Benzazepines; Brain Stem Neoplasms; Disease Models, Animal; Drug Synergism; Glioma; Humans; Hydroxamic Acids; Indoles; Panobinostat; Pyrimidines; Sequence Analysis, RNA; Xenograft Model Antitumor Assays

Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.

Topics: Animals; Apoptosis; Benzazepines; Brain Stem Neoplasms; Cell Line, Tumor; Cell Proliferation; Child; Gene Expression Regulation, Neoplastic; Glioma; Histones; Humans; Jumonji Domain-Containing Histone Demethylases; Methylation; Mice; Pyrimidines; Xenograft Model Antitumor Assays

Diffuse intrinsic pontine glioma is a uniformly lethal malignant tumor of infancy with no effective therapies. A new study reveals that inhibition of JMJD3 has robust antitumor activity in diffuse intrinsic pontine glioma xenografts.

Topics: Animals; Apoptosis; Benzazepines; Brain Stem Neoplasms; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioma; Histones; Humans; Jumonji Domain-Containing Histone Demethylases; Pyrimidines