2. Academic Validation
  3. GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant

GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant

  • Cancer Cell. 2024 Aug 27:S1535-6108(24)00305-2. doi: 10.1016/j.ccell.2024.08.006.
Ilon Liu 1,  Gustavo Alencastro Veiga Cruzeiro 2,  Lynn Bjerke 3,  Rebecca F Rogers 3,  Yura Grabovska 3,  Alexander Beck 4,  Alan Mackay 3,  Tara Barron 5,  Olivia A Hack 2,  Michael A Quezada 5,  Valeria Molinari 3,  McKenzie L Shaw 2,  Marta Perez-Somarriba 6,  Sara Temelso 3,  Florence Raynaud 7,  Ruth Ruddle 7,  Eshini Panditharatna 2,  Bernhard Englinger 8,  Hafsa M Mire 2,  Li Jiang 2,  Andrezza Nascimento 2,  Jenna LaBelle 2,  Rebecca Haase 2,  Jacob Rozowsky 2,  Sina Neyazi 2,  Alicia-Christina Baumgartner 2,  Sophia Castellani 2,  Samantha E Hoffman 2,  Amy Cameron 9,  Murry Morrow 9,  Quang-De Nguyen 9,  Giulia Pericoli 10,  Sibylle Madlener 11,  Lisa Mayr 11,  Christian Dorfer 12,  Rene Geyeregger 13,  Christopher Rota 14,  Gerda Ricken 15,  Keith L Ligon 16,  Sanda Alexandrescu 17,  Rodrigo T Cartaxo 18,  Benison Lau 18,  Santhosh Uphadhyaya 18,  Carl Koschmann 18,  Emelie Braun 19,  Miri Danan-Gotthold 19,  Lijuan Hu 19,  Kimberly Siletti 19,  Erik Sundström 20,  Rebecca Hodge 21,  Ed Lein 21,  Sameer Agnihotri 22,  David D Eisenstat 23,  Simon Stapleton 24,  Andrew King 25,  Cristina Bleil 26,  Angela Mastronuzzi 10,  Kristina A Cole 27,  Angela J Waanders 28,  Angel Montero Carcaboso 29,  Ulrich Schüller 30,  Darren Hargrave 31,  Maria Vinci 10,  Fernando Carceller 32,  Christine Haberler 15,  Irene Slavc 11,  Sten Linnarsson 19,  Johannes Gojo 33,  Michelle Monje 34,  Chris Jones 35,  Mariella G Filbin 36
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin und Humboldt-Universität zu Berlin, 10117 Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, 10117 Berlin, Germany.
  • 2 Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 3 Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey SM2 5 NG, UK.
  • 4 Center for Neuropathology, Ludwig-Maximilians-University, 81377 Munich, Germany.
  • 5 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 6 Children & Young People's Unit, Royal Marsden Hospital NHS Trust, Sutton, Surrey SM2 5 NG, UK.
  • 7 Division of Cancer Therapeutics, The Institute of Cancer Research, London SW7 3RK, UK.
  • 8 Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
  • 9 Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 10 Department of Onco-haematology, Gene and Cell Therapy, Bambino Gesù Children's Hospital-IRCCS, 00165 Rome, Italy.
  • 11 Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
  • 12 Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria.
  • 13 Clinical Cell Biology, Children's Cancer Research Institute (CCRI), Vienna 1090, Austria.
  • 14 Department of Neurobiology, Harvard Medical School, Boston, MA 02215, USA.
  • 15 Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna 1090, Austria.
  • 16 Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 17 Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 18 Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
  • 19 Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden.
  • 20 Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, 17177 Stockholm, Sweden.
  • 21 Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • 22 Departments of Neurosurgery and Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
  • 23 Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
  • 24 Department of Neurosurgery, St George's Hospital NHS Trust, London SW17 0QT, UK.
  • 25 Department of Neuropathology, King's College Hospital NHS Trust, London SE5 9RS, UK.
  • 26 Department of Neurosurgery, King's College Hospital NHS Trust, London SE5 9RS, UK.
  • 27 Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 28 Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
  • 29 Laboratory of Molecular Oncology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain.
  • 30 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
  • 31 University College London Great Ormond Street Institute for Child Health, London WC1N 1EH, UK.
  • 32 Children & Young People's Unit, Royal Marsden Hospital NHS Trust, Sutton, Surrey SM2 5 NG, UK; Division of Clinical Studies, The Institute of Cancer Research, London SW7 3RK, UK.
  • 33 Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
  • 34 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA, USA.
  • 35 Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey SM2 5 NG, UK. Electronic address: chris.jones@icr.ac.uk.
  • 36 Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: mariella.filbin@childrens.harvard.edu.
PMID: 39232581 DOI: 10.1016/j.ccell.2024.08.006
Abstract

Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.

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