Childhood Cancer Data Initiative Annual Symposium (Abstract Registration): Submission #87

serial: '87'
sid: '193902'
uuid: 58dc47f1-b37f-4413-97a7-b57f03bb5ee2
uri: /nci/ccdisymposium/abstract
created: '1788555197'
completed: '1788556349'
changed: '1788556349'
in_draft: '0'
current_page: ''
remote_addr: 10.208.24.244
uid: '0'
langcode: en
webform_id: ccdi_symposium_abstract
entity_type: node
entity_id: '2139'
locked: '0'
sticky: '0'
notes: ''
metatag: meta
data:
  authors_:
    - add_author_degree: Ph.D
      add_author_first_name: Balakrishna
      add_author_last_name: Koneru
      add_author_middle: ''
      add_author_organization: 'Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
    - add_author_degree: Ph.D
      add_author_first_name: Nighat
      add_author_last_name: Noureen
      add_author_middle: ''
      add_author_organization: 'Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
    - add_author_degree: Ph.D
      add_author_first_name: Ashly
      add_author_last_name: Hindle
      add_author_middle: ''
      add_author_organization: 'Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
    - add_author_degree: MS
      add_author_first_name: Kristyn
      add_author_last_name: Mccoy
      add_author_middle: ''
      add_author_organization: 'Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
    - add_author_degree: BS
      add_author_first_name: Jonas
      add_author_last_name: Nance
      add_author_middle: ''
      add_author_organization: 'Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
    - add_author_degree: BS
      add_author_first_name: Diana
      add_author_last_name: Ixtlamati-Nava
      add_author_middle: ''
      add_author_organization: 'Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
    - add_author_degree: BS
      add_author_first_name: Charles
      add_author_last_name: Zhu
      add_author_middle: ''
      add_author_organization: 'Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
    - add_author_degree: BS
      add_author_first_name: Tenley
      add_author_last_name: Lehman
      add_author_middle: ''
      add_author_organization: 'Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
    - add_author_degree: M.D.
      add_author_first_name: 'Mohamad '
      add_author_last_name: Rahawan
      add_author_middle: Al
      add_author_organization: 'Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
    - add_author_degree: M.D.
      add_author_first_name: Yael
      add_author_last_name: Mosse
      add_author_middle: P
      add_author_organization: 'Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA'
    - add_author_degree: M.D.
      add_author_first_name: John
      add_author_last_name: Maris
      add_author_middle: M
      add_author_organization: 'Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA'
    - add_author_degree: M.D.
      add_author_first_name: Shahab
      add_author_last_name: Asgharzadeh
      add_author_middle: ''
      add_author_organization: "Children's Hospital of Los Angeles, Los Angeles, CA, USA"
    - add_author_degree: M.D.
      add_author_first_name: Araz
      add_author_last_name: Marachelian
      add_author_middle: ''
      add_author_organization: "Children's Hospital of Los Angeles, Los Angeles, CA, USA"
    - add_author_degree: M.D.
      add_author_first_name: Meredith
      add_author_last_name: Irwin
      add_author_middle: S
      add_author_organization: 'Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada'
    - add_author_degree: M.D.
      add_author_first_name: Suzanne
      add_author_last_name: Shusterman
      add_author_middle: ''
      add_author_organization: 'Dana-Farber/Harvard Cancer Center, Boston, MA, USA  '
    - add_author_degree: M.D.
      add_author_first_name: Stephen
      add_author_last_name: Roberts
      add_author_middle: S
      add_author_organization: 'Oregon Health and Science University, Portland, OR USA'
    - add_author_degree: PharmD
      add_author_first_name: Min
      add_author_last_name: Kang
      add_author_middle: H
      add_author_organization: 'Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
    - add_author_degree: 'M.D. Ph.D'
      add_author_first_name: Patrick
      add_author_last_name: Reynolds
      add_author_middle: ''
      add_author_organization: 'Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA'
  abstract: |-
    Background: Patient-derived models of neuroblastoma that recapitulate therapy resistance in patients are essential for defining resistance mechanisms.  We established and characterized patient derived xenografts (PDXs) and patient derived cell lines (PDCLs) from neuroblastoma patients with progressive disease established post-mortem (PD-PM).

    Methods: Tumor and blood samples were cultured and/or xenografted in NOD SCIDγ mice. PDCLs and PDXs were validated by STR profiling. Mutations were identified by whole-exome sequencing and telomere maintenance mechanisms by TERT qPCR, C-circle assay, and TERT break-apart FISH. Therapeutic responses were evaluated in subcutaneous xenografts.

    Results: PD-PM specimens showed higher engraftment rates as xenografts (68%; 21/31 specimens, 83% for PD-PM blood specimens) and had higher take rates as PDCLs (54%, 25/46 specimens) compared to diagnosis (Dx, 17%) or progressive disease (PD, 11%, P<0.001) specimens. PD-PM PDXs had higher mutation burdens than Dx PDXs (P=0.026); 33% harbored activating ALK mutations and 33% mutations in other RAS-MAPK genes. Of 20 high TERT-expressing PD-PM PDXs, 13 had MYCN amplification and 4 MYCN-non-amplified PDXs had TERT rearrangements. One PD-PM PDX was ALT-positive. Temozolomide + irinotecan responses were shorter in 3 PD-PM than Dx and PD PDXs (P<0.001). In a PD-PM PDX, O6-BG reversed temozolomide + irinotecan resistance (P=0.002), while nanoliposomal irinotecan extended event-free survival compared to irinotecan (P=0.003).

    Conclusions: PD-PM PDXs activate ALK or RAS-MAPK signaling, manifest high levels of chemoresistance, and provide models to study reversing neuroblastoma drug resistance.  The Children’s Oncology Group (COG) panel of PDXs is freely available from the Alex's Lemonade Stand Foundation (ALSF)/COG Childhood Cancer Repository (https://cccells.org).
  abstract_title_: 'Neuroblastoma Patient-Derived Xenografts and Cell Lines from Postmortem Blood as Models to Understand and Reverse Therapy Resistance'
  email_address_: balakrishna.koneru@ttuhsc.edu
  institution_: 'Texas Tech University Health Sciences Center'
  presenting_author_: 'BALAKRISHNA KONERU'