New potential target found for diffuse intrinsic pontine glioma (DIPG)
An international research team has uncovered details of deadly H3K27M-mutated pediatric gliomas, as well as a possible targeted therapy. The findings appeared in the scientific journal Nature Medicine "EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas".
"The Danish group created a mouse model based on the same genetic changes in a protein named histone –H3K27M- found in the human brain tumor. This enabled to reproduce the patient tumor," said Angel Montero Carcaboso, researcher at Sant Joan de Déu and coauthor of the study. "The findings in the mouse cells were validated in the DIPG and pediatric glioma patient cohorts and in cell models created at Sant Joan de Déu from patients biopsies". The lead author of the study was Faizaan Mohammad and the senior author Kristian Helin, both from BRIC. Other coauthors at Sant Joan de Déu were Nagore Gené Olaciregui, Cinzia Lavarino, Mariona Suñol, Carmen de Torres and Jaume Mora.
Using the H3K27M-mutated mouse cells and primary patient-derived DIPG cell models, the researchers show that H3K27M-expressing tumors require a complex of proteins named PRC2 for proliferation and that drugs that inhibit EZH2 (a member of the PRC2 complex) abolish tumor cell growth in vitro (in culture) through a mechanism that is dependent on the induction of the tumor-suppressor protein p16INK4A. Future steps of the project are to validate in vivo the activity of potential EZH2 inhibitors, using animal models like DIPG xenografts (mice with engrafted human tumors in the brain).
The research at Sant Joan de Déu was funded by the Fondo Alicia Pueyo, AECC Scientific Foundation, European Union Seventh Framework Programme (FP7/2007-2013) under Marie Curie International Reintegration Grant (PIRG-08-GA-2010-276998) and ISCIII-FEDER (CP13/00189).
*Image: DIPG in the protrusion of a mouse brain and detail of tumor markers. Image source: Mohammad F, Weissmann S, Leblanc B, Pandey DP, Højfeldt JW, Comet I, Zheng C, Johansen JV, Rapin N, Porse BT, Tvardovskiy A, Jensen ON, Olaciregui NG, Lavarino C, Suñol M, de Torres C, Mora J, Carcaboso AM, Helin K. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med. 2017 Feb 27.