Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma

Avishay Spitzer; Simon Gritsch; Masashi Nomura; Alexander Jucht; Jerome Fortin; Ramya Raviram; Hannah R Weisman; L Nicolas Gonzalez Castro; Nicholas Druck; Rony Chanoch-Myers; John J Y Lee; Ravindra Mylvaganam; Rachel Lee Servis; Jeremy Man Fung; Christine K Lee; Hiroaki Nagashima; Julie J Miller; Isabel Arrillaga-Romany; David N Louis; Hiroaki Wakimoto; Will Pisano; Patrick Y Wen; Tak W Mak; Marc Sanson; Mehdi Touat; Dan A Landau; Keith L Ligon; Daniel P Cahill; Mario L Suvà; Itay Tirosh

doi:10.1016/j.ccell.2024.03.008

Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma

Cancer Cell. 2024 Apr 2:S1535-6108(24)00093-X. doi: 10.1016/j.ccell.2024.03.008. Online ahead of print.

Authors

Avishay Spitzer¹, Simon Gritsch², Masashi Nomura³, Alexander Jucht³, Jerome Fortin⁴, Ramya Raviram⁵, Hannah R Weisman³, L Nicolas Gonzalez Castro⁶, Nicholas Druck³, Rony Chanoch-Myers⁷, John J Y Lee³, Ravindra Mylvaganam⁸, Rachel Lee Servis⁸, Jeremy Man Fung⁸, Christine K Lee⁹, Hiroaki Nagashima⁹, Julie J Miller¹⁰, Isabel Arrillaga-Romany¹¹, David N Louis⁸, Hiroaki Wakimoto⁹, Will Pisano¹², Patrick Y Wen¹³, Tak W Mak¹⁴, Marc Sanson¹⁵, Mehdi Touat¹⁶, Dan A Landau⁵, Keith L Ligon¹⁷, Daniel P Cahill¹⁸, Mario L Suvà¹⁹, Itay Tirosh²⁰

Affiliations

¹ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel; Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
² Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
³ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada.
⁵ New York Genome Center, New York, NY, USA; Weill Cornell Medicine, New York, NY, USA.
⁶ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel.
⁸ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁹ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹⁰ Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹¹ Departments of Neurology and Radiation Oncology, Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
¹² Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
¹³ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
¹⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China; Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
¹⁵ Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
¹⁶ Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁷ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: keith_ligon@dfci.harvard.edu.
¹⁸ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: cahill@mgh.harvard.edu.
¹⁹ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: suva.mario@mgh.harvard.edu.
²⁰ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel. Electronic address: itay.tirosh@weizmann.ac.il.

PMID: 38579724
DOI: 10.1016/j.ccell.2024.03.008

Abstract

A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.

Keywords: IDH1; differentiation therapy; glioma; ivosidenib; oligodendroglioma; single cell RNA-seq; vorasidenib.