By Ilon Liu and Mariella G. Filbin,

High-grade gliomas are lethal brain tumors that commonly arise from, and resemble, glial cell progenitors. Among these, H(istone)3G34R/V-mutant diffuse hemispheric gliomas present a specific molecular group that occur in a time- and location specific context (the cerebral hemispheres of adolescent and young adult patients), suggesting a distinct neurodevelopmental context from which they originate.

In our studies we found that these gliomas consist of diverse tumor cells that not only resemble astrocytic glial cell types, but also mimick GABAergic interneurons and their progenitors, thereby pointing towards an early bi-potent progenitor cell of origin of these tumors. Interestingly, GABAergic interneuron-like tumor cells also form nests within the tissue that mirror normal human embryonal development of GABAergic interneurons in the second trimester, and are further capable of even producing GABA. To what extent these tumor cells functionally resemble their normal interneuron counterparts and which implications this has for their interactions within the rest of the tumor and neural environment, present some of many exciting cancer neuroscience questions for future follow-up studies.

Schematic of neurodevelopmental cell states and their hierarchy detected in H3G34R/V-mutant glioma.

Furthermore, this finding opens up new avenues to specifically target the neurodevelopmental origin of these H3G34R/V-mutant gliomas, against which targeted therapies have so far been lacking. Through combining our findings with a functional CRISPR-screen in patient-derived cell lines, we found that tumor cells depend on the continued expression of interneuronal progenitor marker genes for their growth, which prevents them from differentiating into fully mature post-mitotic interneurons. Among these genes, we identified CDK6 as a readily druggable target – inhibition or depletion of which leads to enhanced differentiation towards mature interneuronal states, reduced tumor growth, and prolonged survival of mice with these brain tumors. Based on these promising preclinical data, we also treated a first patient with H3G34R/V-mutant glioma, after two standard treatments had failed, with the CDK4/6-inhibitor ribociclib, which led to disease stabilization for an exceptional period of time.

These results now pave the way for many exciting follow-up questions and studies. These range from above mentioned fundamental cancer neuroscience questions, to translational implications including the testing of combination therapies with CDK6-inhibitors and the implementation of early-phase clinical trials towards the ultimate goal of finding a cure for these deadly cancers.

Ilon Liu was a post-doctoral fellow in the Filbin laboratory and is now a clinician-scientist and group leader at the Department of Neurology with Experimental Neurology at the Charité University Hospital in Berlin, Germany.

Mariella G. Filbin is an Associate Professor of Pediatrics at Harvard Medical School, Jan Paradise Chair in Brain Cancer Research, Co-Director of the Brain Tumor Center of Excellence, Research Director of the Pediatric Neuro-Oncology Program at Dana-Farber Cancer Institute, and Attending Physician in Pediatric Hematology/Oncology at Boston Children’s Hospital.

Learn more in the original research article:
GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant
Liu I, Alencastro Veiga Cruzeiro G, Bjerke L, Rogers RF, Grabovska Y, Beck A, Mackay A, Barron T, Hack OA, Quezada MA, Molinari V, Shaw ML, Perez-Somarriba M, Temelso S, Raynaud F, Ruddle R, Panditharatna E, Englinger B, Mire HM, Jiang L, Nascimento A, LaBelle J, Haase R, Rozowsky J, Neyazi S, Baumgartner AC, Castellani S, Hoffman SE, Cameron A, Morrow M, Nguyen QD, Pericoli G, Madlener S, Mayr L, Dorfer C, Geyeregger R, Rota C, Ricken G, Ligon KL, Alexandrescu S, Cartaxo RT, Lau B, Uphadhyaya S, Koschmann C, Braun E, Danan-Gotthold M, Hu L, Siletti K, Sundström E, Hodge R, Lein E, Agnihotri S, Eisenstat DD, Stapleton S, King A, Bleil C, Mastronuzzi A, Cole KA, Waanders AJ, Montero Carcaboso A, Schüller U, Hargrave D, Vinci M, Carceller F, Haberler C, Slavc I, Linnarsson S, Gojo J, Monje M, Jones C, Filbin MG. Cancer Cell. 2024 Aug 27:S1535-6108(24)00305-2.