De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma

Diana D Shi; Milan R Savani; Michael M Levitt; Adam C Wang; Jennifer E Endress; Cylaina E Bird; Joseph Buehler; Sylwia A Stopka; Michael S Regan; Yu-Fen Lin; Vinesh T Puliyappadamba; Wenhua Gao; Januka Khanal; Laura Evans; Joyce H Lee; Lei Guo; Yi Xiao; Min Xu; Bofu Huang; Rebecca B Jennings; Dennis M Bonal; Misty S Martin-Sandoval; Tammie Dang; Lauren C Gattie; Amy B Cameron; Sungwoo Lee; John M Asara; Harley I Kornblum; Tak W Mak; Ryan E Looper; Quang-De Nguyen; Sabina Signoretti; Stefan Gradl; Andreas Sutter; Michael Jeffers; Andreas Janzer; Mark A Lehrman; Lauren G Zacharias; Thomas P Mathews; Julie-Aurore Losman; Timothy E Richardson; Daniel P Cahill; Ralph J DeBerardinis; Keith L Ligon; Lin Xu; Peter Ly; Nathalie Y R Agar; Kalil G Abdullah; Isaac S Harris; William G Kaelin Jr; Samuel K McBrayer

doi:10.1016/j.ccell.2022.07.011

De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma

Cancer Cell. 2022 Sep 12;40(9):939-956.e16. doi: 10.1016/j.ccell.2022.07.011. Epub 2022 Aug 18.

Authors

Diana D Shi¹, Milan R Savani², Michael M Levitt³, Adam C Wang⁴, Jennifer E Endress⁵, Cylaina E Bird⁶, Joseph Buehler³, Sylwia A Stopka⁷, Michael S Regan⁸, Yu-Fen Lin⁹, Vinesh T Puliyappadamba³, Wenhua Gao⁴, Januka Khanal⁴, Laura Evans¹⁰, Joyce H Lee⁴, Lei Guo¹¹, Yi Xiao³, Min Xu³, Bofu Huang⁴, Rebecca B Jennings¹², Dennis M Bonal¹³, Misty S Martin-Sandoval³, Tammie Dang¹⁴, Lauren C Gattie¹⁵, Amy B Cameron¹³, Sungwoo Lee¹⁶, John M Asara¹⁷, Harley I Kornblum¹⁸, Tak W Mak¹⁹, Ryan E Looper²⁰, Quang-De Nguyen¹³, Sabina Signoretti¹², Stefan Gradl²¹, Andreas Sutter²¹, Michael Jeffers²², Andreas Janzer²¹, Mark A Lehrman¹⁴, Lauren G Zacharias³, Thomas P Mathews³, Julie-Aurore Losman⁴, Timothy E Richardson²³, Daniel P Cahill²⁴, Ralph J DeBerardinis²⁵, Keith L Ligon²⁶, Lin Xu²⁷, Peter Ly⁹, Nathalie Y R Agar²⁸, Kalil G Abdullah²⁹, Isaac S Harris³⁰, William G Kaelin Jr³¹, Samuel K McBrayer³²

Affiliations

¹ Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA 02215, USA; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³ Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
⁵ Ludwig Cancer Center, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
⁷ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁸ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁹ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁰ Bayer HealthCare Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
¹¹ Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹³ Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
¹⁴ Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁵ Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
¹⁶ New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.
¹⁷ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
¹⁸ Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Behavioral Sciences, and Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90024, USA.
¹⁹ The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON M5G 2M9, Canada; The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
²⁰ Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
²¹ Bayer AG, Muellerstrasse 178, 13353 Berlin, Germany.
²² Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ 07981, USA.
²³ Department of Pathology, Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX 78229, USA.
²⁴ Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
²⁵ Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
²⁶ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pathology, Children's Hospital Boston, Boston, MA 02115, USA.
²⁷ Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
²⁸ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
²⁹ Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Hillman Comprehensive Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
³⁰ Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
³¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: william_kaelin@dfci.harvard.edu.
³² Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. Electronic address: samuel.mcbrayer@utsouthwestern.edu.

Abstract

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.

Keywords: DHODH; IDH; cancer metabolism; genetically engineered mouse model; glioma; isocitrate dehydrogenase; pyrimidine nucleotides.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Neoplasms* / drug therapy
Brain Neoplasms* / genetics
Enzyme Inhibitors / therapeutic use
Glioma* / drug therapy
Glioma* / genetics
Isocitrate Dehydrogenase / genetics
Isocitrate Dehydrogenase / metabolism
Leukemia*
Mice
Mutation
Pyrimidines / pharmacology
Pyrimidines / therapeutic use
Salicylanilides
Triazoles

Substances

Enzyme Inhibitors
Pyrimidines
Salicylanilides
Triazoles
Isocitrate Dehydrogenase
orludodstat

Abstract

Publication types

MeSH terms

Substances

Grants and funding