A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma

Sharmistha Pal; Jakub P Kaplan; Huy Nguyen; Sylwia A Stopka; Milan R Savani; Michael S Regan; Quang-De Nguyen; Kristen L Jones; Lisa A Moreau; Jingyu Peng; Marina G Dipiazza; Andrew J Perciaccante; Xiaoting Zhu; Bradley R Hunsel; Kevin X Liu; Sanda Alexandrescu; Rachid Drissi; Mariella G Filbin; Samuel K McBrayer; Nathalie Y R Agar; Dipanjan Chowdhury; Daphne A Haas-Kogan

doi:10.1016/j.ccell.2022.07.012

A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma

Cancer Cell. 2022 Sep 12;40(9):957-972.e10. doi: 10.1016/j.ccell.2022.07.012. Epub 2022 Aug 18.

Authors

Sharmistha Pal¹, Jakub P Kaplan¹, Huy Nguyen¹, Sylwia A Stopka², Milan R Savani³, Michael S Regan⁴, Quang-De Nguyen⁵, Kristen L Jones⁵, Lisa A Moreau⁶, Jingyu Peng⁷, Marina G Dipiazza⁴, Andrew J Perciaccante⁴, Xiaoting Zhu⁸, Bradley R Hunsel¹, Kevin X Liu⁹, Sanda Alexandrescu¹⁰, Rachid Drissi⁸, Mariella G Filbin¹¹, Samuel K McBrayer¹², Nathalie Y R Agar¹³, Dipanjan Chowdhury¹⁴, Daphne A Haas-Kogan¹⁵

Affiliations

¹ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
² Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
³ Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
⁵ Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
⁶ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁷ Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁸ Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
⁹ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Radiation Oncology, Brigham and Women's Hospital, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
¹⁰ Department of Pathology, Harvard Medical School Boston, Boston Children's Hospital, 300 Longwood Avenue, Bader 104, Boston, MA 02115, USA.
¹¹ Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA.
¹² 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.
¹³ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁴ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹⁵ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Radiation Oncology, Brigham and Women's Hospital, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].

Abstract

Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pyrimidine biosynthesis pathway. A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5'-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks-an "on-target" effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.

Keywords: ATR; BAY2402234; DHODH; DPYD; de novo pyrimidine synthesis; diffuse intrinsic pontine glioma; diffuse midline glioma; elimusertib; pyrimidine degradation; replication stress.

Publication types

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

MeSH terms

Animals
Glioma* / drug therapy
Glioma* / genetics
Humans
Mice
Pyrimidines*
Uridine / metabolism
Uridine / pharmacology

Substances

Pyrimidines
Uridine

Abstract

Publication types

MeSH terms

Substances

Grants and funding