2. Academic Validation
  3. NTRK Fusions Can Co-Occur With H3K27M Mutations and May Define Druggable Subclones Within Diffuse Midline Gliomas

NTRK Fusions Can Co-Occur With H3K27M Mutations and May Define Druggable Subclones Within Diffuse Midline Gliomas

  • J Neuropathol Exp Neurol. 2021 Mar 22;80(4):345-353. doi: 10.1093/jnen/nlab016.
Nathan A Dahl 1 2 3,  Andrew M Donson 1 2,  Bridget Sanford 2,  Dong Wang 1 2,  Faye M Walker 1 2,  Ahmed Gilani 2 4,  Nicholas K Foreman 1 2 3 5,  Christopher L Tinkle 6,  Suzanne J Baker 7,  Lindsey M Hoffman 8,  Sujatha Venkataraman 1 2,  Rajeev Vibhakar 1 2 3 5
Affiliations

Affiliations

  • 1 From the Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA.
  • 2 Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
  • 3 Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado, USA.
  • 4 Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, USA.
  • 5 Department of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado, USA.
  • 6 Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 7 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 8 Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.
PMID: 33749791 DOI: 10.1093/jnen/nlab016
Abstract

Diffuse midline gliomas (DMGs) are incurable pediatric tumors with extraordinarily limited treatment options. Decades of clinical trials combining conventional chemotherapies with radiation therapy have failed to improve these outcomes, demonstrating the need to identify and validate druggable biologic targets within this disease. NTRK1/2/3 fusions are found in a broad range of pediatric cancers, including high-grade gliomas and a subset of DMGs. Phase 1/2 studies of Trk inhibitors have demonstrated good tolerability, effective CNS penetration, and promising objective responses across all patients with Trk fusion-positive cancers, but their use has not been explored in Trk fusion-positive DMG. Here, we report 3 cases of NTRK fusions co-occurring within H3K27M-positive pontine diffuse midline gliomas. We employ a combination of single-cell and bulk transcriptome Sequencing from Trk fusion-positive DMG to describe the phenotypic consequences of this co-occurring alteration. We then use ex vivo short-culture assays to evaluate the potential response to Trk inhibition in this disease. Together, these data highlight the importance of routine molecular characterization of these highly aggressive tumors and identify a small subset of patients that may benefit from currently available targeted therapies.

Keywords

Diffuse intrinsic pontine glioma; Diffuse midline glioma; Entrectinib; H3K27M; Larotrectinib; NTRK.

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