EPCO-20. MUTANT IDH INHIBITORS INDUCE LINEAGE DIFFERENTIATION IN IDH-MUTANT OLIGODENDROGLIOMA
Abstract IDH-mutant gliomas exhibit variable responses to mutant-IDH inhibitor (IDHi) therapy; yet, the molecular mechanisms underlying these responses remain poorly understood. Here, we investigate the cellular underpinnings of response by leveraging single cell/nuclei RNA-sequencing of on-treatment IDH-mutant oligodendroglioma tumor samples resected from three patients who benefited clinically from treatment. We integrate these findings with single cell and bulk RNA-seq data from independent cohorts and experimental models. We find that IDHi treatment promotes robust differentiation towards the astrocytic lineage, accompanied by stem-like cell depletion and reduced proliferation. Notably, NOTCH1 mutations are associated with impaired astrocytic differentiation, potentially negatively impacting response to IDHi. This study unveils the differentiating effects of IDHi on oligodendroglioma cellular hierarchies and identifies a potential genetic marker for optimizing patient selection. Paper was recently published in Cancer Cell (10.1016/j.ccell.2024.03.008).
Authors
- Tak W. Mak (ORCID: https://orcid.org/0000-0001-6766-861X)
- Itay Tirosh (ORCID: https://orcid.org/0000-0001-5477-2987)
- L. Nicolas Gonzalez Castro (ORCID: https://orcid.org/0000-0001-7699-5188)
- Hiroaki Wakimoto (ORCID: https://orcid.org/0000-0001-8225-241X)
- Keith Lloyd Ligon (ORCID: https://orcid.org/0000-0002-7733-600X)
- Alexander Jucht
- Mario L. Suvà (ORCID: https://orcid.org/0000-0001-9898-5351)
- Hiroaki Nagashima (ORCID: https://orcid.org/0000-0003-0685-7382)
- Julie J. Miller (ORCID: https://orcid.org/0000-0002-1288-593X)
- Daniel P. Cahill (ORCID: https://orcid.org/0000-0003-2552-6546)
- Masashi Nomura (ORCID: https://orcid.org/0000-0001-6095-7849)
- Christine K. Lee (ORCID: https://orcid.org/0000-0003-1422-4606)
- Will Pisano
- David N. Louis (ORCID: https://orcid.org/0000-0002-9423-4099)
- Patrick Yung Wen (ORCID: https://orcid.org/0000-0002-0774-7700)
- Ramya Raviram (ORCID: https://orcid.org/0000-0002-5450-1455)
- Isabel Arrillaga‐Romany (ORCID: https://orcid.org/0000-0001-5951-1225)
- Avishay Spitzer (ORCID: https://orcid.org/0000-0001-6551-9338)
- Rony Chanoch-Myers (ORCID: https://orcid.org/0000-0002-8197-5795)
- John J. Y. Lee (ORCID: https://orcid.org/0000-0002-7967-3384)
- Ravindra Mylvaganam (ORCID: https://orcid.org/0000-0001-5336-6557)
- Hannah Weisman (ORCID: https://orcid.org/0000-0002-6874-9339)
- Jeremy Man Fung
- Simon Gritsch (ORCID: https://orcid.org/0000-0001-5682-5712)
- Nicholas Druck
- Marc Sanson (ORCID: https://orcid.org/0000-0002-1813-8476)
- Jérôme Fortin
- Dan A. Landau (ORCID: https://orcid.org/0000-0003-2346-9541)
- Rachel L. Servis
- Mehdi Touat (ORCID: https://orcid.org/0000-0002-2340-5604)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Montreal Neurological Institute and Hospital (CA)
- Centre National de la Recherche Scientifique (FR)
- University Health Network (CA)
- Harvard University (US)
- Inserm (FR)
- Cornell University (US)
- Tel Aviv Sourasky Medical Center (IL)
- Hong Kong Science and Technology Parks Corporation (HK)
- Princess Margaret Cancer Centre (CA)
- Sorbonne Université (FR)
- Massachusetts General Hospital (US)
- Assistance Publique – Hôpitaux de Paris (FR)
- Center for Neuro-Oncology (US)
- Dana-Farber Cancer Institute (US)
- Center for Cancer Research (US)
- New York Genome Center (US)
- Institut du Cerveau (FR)
- Weill Cornell Medicine (US)
- McGill University (CA)
- Weizmann Institute of Science (IL)
Publication Details
- Journal
- Neuro-Oncology
- Published
- 2024-11-01
- DOI
- https://doi.org/10.1093/neuonc/noae165.0019
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00