GSE184786
Effects of the Combination Therapy of a CDK4/6 and a MEK inhibitor in a Mouse Model of Diffuse Midline Glioma
Diffuse intrinsic pontine glioma (DIPG) arises in the brainstem of children, leading tumor-related death among children. A heterozygous histone H3.3K27M mutation has been shown to occur in ~80% of DIPGs, and results in brainstem gliomagenesis. There is no clinical trial for the patients with DIPG that proved to prolong survival time so far. Recently, CDK4/6 inhibitor showed feasibility and early therapeutic effect against DIPG. Also, recent research with human DIPG specimens have detected the MAPK pathway highly activated. Here, we evaluated a novel combination therapy with CDK4/6 inhibitor and MEK inhibitor to the mouse DIPG model.  In order to generate DIPG-bearing mice, we are using the RCAS/Tv-a system, with which we are able to target specific genetic alterations in RCAS viruses (avian retroviruses) to specific cells-of-origin using transgenic Tv-a-expressing mice (Tv-a being the receptor for RCAS viruses). We injected P3-P5 Nestin-Tv-a;p53fl/fl mice (C56Bl/6 background) with RCAS-PDGF-A + RCAS-H3.3K27M, and RCAS-Cre. The mice are treated with vehicle (methylcellurose), ribociclib as monotherapy, trametinib as monotherapy, and ribociclib and combination as combination. For short-term use, tumor tissues treated with ribociclib showed cytostatic effect, and those treated with trametinib showed cytotoxic effect, and those with combination showed both. Long-term use showed that combination therapy modestly prolonged mice survival compared with vehicle. Therefore, we need to find how DIPG showed registence to the long-term chemotherapy. Overall design: Examination of gene expression differences in mouse DIPGs treated with vehicle, ribociclib, trametinib, and ribociclib and trametinib as combination