GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant PMID: 39232581

ADC Targets in Oncology

2026-04-10

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

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: [email protected].
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: [email protected].

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.