2. Academic Validation
  3. An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma

  • Cell Rep. 2023 Dec 18;43(1):113557. doi: 10.1016/j.celrep.2023.113557.
Stephanie M Casillo 1,  Taylor A Gatesman 1,  Akanksha Chilukuri 1,  Srinidhi Varadharajan 2,  Brenden J Johnson 1,  Daniel R David Premkumar 1,  Esther P Jane 1,  Tritan J Plute 1,  Robert F Koncar 1,  Ann-Catherine J Stanton 1,  Carlos A O Biagi-Junior 3,  Callie S Barber 1,  Matthew E Halbert 1,  Brian J Golbourn 1,  Katharine Halligan 4,  Andrea F Cruz 1,  Neveen M Mansi 1,  Allison Cheney 5,  Steven J Mullett 6,  Clinton Van't Land 7,  Jennifer L Perez 8,  Max I Myers 1,  Nishant Agrawal 1,  Joshua J Michel 9,  Yue-Fang Chang 1,  Olena M Vaske 5,  Antony MichaelRaj 1,  Frank S Lieberman 10,  James Felker 11,  Sruti Shiva 12,  Kelsey C Bertrand 2,  Nduka Amankulor 13,  Costas G Hadjipanayis 1,  Kalil G Abdullah 1,  Pascal O Zinn 1,  Robert M Friedlander 1,  Taylor J Abel 1,  Javad Nazarian 14,  Sriram Venneti 15,  Mariella G Filbin 3,  Stacy L Gelhaus 16,  Stephen C Mack 2,  Ian F Pollack 1,  Sameer Agnihotri 17
Affiliations

Affiliations

  • 1 Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
  • 2 Department of Pediatric Hematology and Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 3 Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 4 Division of Hematology Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pittsburgh, PA 15261, USA; Division of Hematology Oncology, Department of Pediatrics, Albany Medical College, Albany, NY 12208, USA.
  • 5 Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; University of California, Santa Cruz Genomics Institute, Santa Cruz, CA 95064, USA.
  • 6 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 7 Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Rangos Metabolic Core Facility, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA.
  • 8 Department of Neurological Surgery, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA.
  • 9 Rangos Flow Cytometry Core Laboratory, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA.
  • 10 Adult Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
  • 11 Pediatric Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
  • 12 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Heart, Lung, Blood, and Vascular Medicine Institute, Department of Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 13 Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 14 Brain Tumor Institute, Children's National Hospital, Washington, DC 20010, USA.
  • 15 Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 16 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA 15224, USA.
  • 17 Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Pediatric Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA. Electronic address: sameer.agnihotri@pitt.edu.
PMID: 38113141 DOI: 10.1016/j.celrep.2023.113557
Abstract

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the Ras pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic Enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Keywords

CP: Cancer; CP: Metabolism; ERK5; H3K27a-DMG; MEF2A; PFKFB3; glioma; glycolysis; metabolism; multi targeted; pediatric; synergy.

Figures
Products