2. Academic Validation
  3. Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma

Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma

  • Cell Rep. 2020 Apr 7;31(1):107485. doi: 10.1016/j.celrep.2020.03.049.
Nathan A Dahl 1,  Etienne Danis 2,  Ilango Balakrishnan 2,  Dong Wang 2,  Angela Pierce 2,  Faye M Walker 2,  Ahmed Gilani 3,  Natalie J Serkova 4,  Krishna Madhavan 2,  Susan Fosmire 2,  Adam L Green 5,  Nicholas K Foreman 6,  Sujatha Venkataraman 2,  Rajeev Vibhakar 7
Affiliations

Affiliations

  • 1 Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, CO, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA. Electronic address: nathan.dahl@childrenscolorado.org.
  • 2 Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, CO, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
  • 3 Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
  • 4 Department of Radiology, University of Colorado School of Medicine, Aurora, CO, USA.
  • 5 Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, CO, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA.
  • 6 Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, CO, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA; Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA.
  • 7 Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, CO, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA; Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA. Electronic address: rajeev.vibhakar@ucdenver.edu.
PMID: 32268092 DOI: 10.1016/j.celrep.2020.03.049
Abstract

Histone 3 gene mutations are the eponymous drivers in diffuse midline gliomas (DMGs), aggressive pediatric brain cancers for which no curative therapy currently exists. These recurrent oncohistones induce a global loss of repressive H3K27me3 residues and broad epigenetic dysregulation. In order to identify therapeutically targetable dependencies within this disease context, we performed an RNAi screen targeting epigenetic/chromatin-associated genes in patient-derived DMG cultures. This identified AFF4, the scaffold protein of the super elongation complex (SEC), as a molecular dependency in DMG. Interrogation of SEC function demonstrates a key role for maintaining clonogenic potential while promoting self-renewal of tumor stem cells. Small-molecule inhibition of SEC using clinically relevant CDK9 inhibitors restores regulatory RNA polymerase II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect both in vitro and in patient-derived xenograft models. These studies present a rationale for further exploration of SEC inhibition as a promising therapeutic approach to this intractable disease.

Keywords

AFF4; AZD4573; CDK9; DIPG; DMG; SEC; atuveciclib; diffuse intrinsic pontine glioma; diffuse midline glioma; super elongation complex.

Figures
Products