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A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma.
Pal, Sharmistha; Kaplan, Jakub P; Nguyen, Huy; Stopka, Sylwia A; Savani, Milan R; Regan, Michael S; Nguyen, Quang-De; Jones, Kristen L; Moreau, Lisa A; Peng, Jingyu; Dipiazza, Marina G; Perciaccante, Andrew J; Zhu, Xiaoting; Hunsel, Bradley R; Liu, Kevin X; Alexandrescu, Sanda; Drissi, Rachid; Filbin, Mariella G; McBrayer, Samuel K; Agar, Nathalie Y R; Chowdhury, Dipanjan; Haas-Kogan, Daphne A.
Affiliation
  • Pal S; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Kaplan JP; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Nguyen H; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Stopka SA; 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.
  • Savani MR; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Regan MS; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Nguyen QD; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
  • Jones KL; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
  • Moreau LA; 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.
  • Peng J; Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Dipiazza MG; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Perciaccante AJ; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Zhu X; 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.
  • Hunsel BR; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Liu KX; 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.
  • Alexandrescu S; Department of Pathology, Harvard Medical School Boston, Boston Children's Hospital, 300 Longwood Avenue, Bader 104, Boston, MA 02115, USA.
  • Drissi R; 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.
  • Filbin MG; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA.
  • McBrayer SK; 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.
  • Agar NYR; 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.
  • Chowdhury D; 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.
  • Haas-Kogan DA; 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: dhaas-kogan@bwh.harvard.edu.
Cancer Cell ; 40(9): 957-972.e10, 2022 09 12.
Article in En | MEDLINE | ID: mdl-35985342
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Glioma Limits: Animals / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2022 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Glioma Limits: Animals / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2022 Document type: Article Affiliation country: Estados Unidos