ArticleClinical cancer research : an official journal of the American Association for Cancer Research2014
Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas.
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109 citing papers in PubMed, 192 citations in OpenAlex.
- Phase II study of safusidenib erbumine in patients with chemotherapy- and radiotherapy-naïve isocitrate dehydrogenase 1-mutated WHO grade 2 gliomas.Neuro-oncology · 2026Trial
- Autophagy inhibition sensitizes radiotherapy responses in high-grade mutant IDH1 glioma.Nature communications · 2026Article
- Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.Cell · 2026Article
- 1p/19q codeletion induces targetable and imageable vulnerabilities in glucose metabolism in oligodendrogliomas.Neuro-oncology · 2026Article
- Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells.Nature chemical biology · 2026Article
- Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.Nature metabolism · 2026Article
- dMMR killer: A conditional suicide gene that preferentially kills DNA mismatch repair-deficient cells.Molecular therapy. Nucleic acids · 2026Article
- Long-term administration of the mutant IDH inhibitor DS-1001b suppresses the growth of IDH1-mutant glioma in vitro and in mouse xenograft models and alters epigenetic profiles.Acta neuropathologica · 2026Article
- Polyphenol-Based Nutritional Strategies Combined With Exercise for Brain Function and Glioma Control: Focus on Epigenetic Modifications, Cognitive Function, Learning and Memory Processes.Food science & nutrition · 2025Review
- HR eye & MMR eye: one-day assessment of DNA repair-defective tumors eligible for targeted therapy.Nature communications · 2025Article
- HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy.Cell · 2025Article
- The molecular history of IDH-mutant astrocytomas without adjuvant treatment.Brain pathology (Zurich, Switzerland) · 2025Article
- Opportunities and challenges for patient-derived models of brain tumors in functional precision medicine.NPJ precision oncology · 2025Review
- Implications of molecular classifications in glioma surgery.Journal of neuro-oncology · 2025Review
- IDH Mutant Cholangiocarcinoma: Pathogenesis, Management, and Future Therapies.Current oncology (Toronto, Ont.) · 2025Review
- Physical activity and glioblastoma: a paradigm shift in neuro-oncology therapy.Frontiers in oncology · 2025Review
- Translational Research Platform for Malignant Central Nervous System Tumors.Neurologia medico-chirurgica · 2024Article
- CDKN2A/B Homozygous Deletion Sensitizes IDH-Mutant Glioma to CDK4/6 Inhibition.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.Science (New York, N.Y.) · 2024Article
- IDH inhibition in gliomas: from preclinical models to clinical trials.Nature reviews. Neurology · 2024Review
49 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 5 institutions in 3 countries.
Hiroaki WakimotoAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Shota TanakaAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
William T CurryAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Franziska LoebelAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Dan ZhaoAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Kensuke TateishiAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Juxiang ChenAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Lindsay K KlofasAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Nina LelicAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
James C KimAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Dora Dias-SantagataAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Leif W EllisenAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Darrell R BorgerAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Sarah-Maria FendtAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Matthew G Vander HeidenAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Tracy T BatchelorAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
A John IafrateAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Daniel P CahillAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.
Andrew S ChiAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium chi.andrew@mgh.harvard.edu cahill@mgh.harvard.edu.
Translational Research in Oncology · FRMassachusetts Institute of Technology · USHarvard University · USMassachusetts General Hospital · USCenter for Neuro-Oncology · US
Funding
Targeting the Vasular SystemP50CA165962 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI KEITH LLOYD LIGON · 2013 to 2026
$33.5MClinical and Molecular Studies of Novel Therapeutics in Malignant Brain TumorsK24CA125440 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI BATCHELOR, TRACY T · 2007 to 2016
$1.9MNCI NIH HHS K24 CA125440NCI NIH HHS P50 CA165962Wellcome Trust
Abstract
purposeIsocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas.
methodsWe prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients.
resultsBy 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored "lineage-defining" mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non-xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months; P = 0.0011).
conclusionA subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. Clin Cancer Res; 20(11); 2898-909. ©2014 AACR.
Indexed as
AnimalsBrain NeoplasmsCell Transformation, NeoplasticDisease-Free SurvivalGas Chromatography-Mass SpectrometryGliomaHeterograftsHumansIn Situ Hybridization, FluorescenceIsocitrate DehydrogenaseKaplan-Meier EstimateMiceMutationOncogenesPhenotypeIsocitrate Dehydrogenase
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