Childhood Cancer Data Initiative Annual Symposium (Abstract Registration): Submission #53

serial: '53'
sid: '150418'
uuid: 0497f474-cdd5-4281-9c88-a4e47fd4229b
uri: /nci/ccdisymposium/abstract
created: '1756504244'
completed: '1756504923'
changed: '1756504923'
in_draft: '0'
current_page: ''
remote_addr: 10.208.28.51
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: PhD
      add_author_first_name: Balakrishna
      add_author_last_name: Koneru
      add_author_middle: ''
      add_author_organization: 'Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA'
    - add_author_degree: PhD
      add_author_first_name: 'Nighat '
      add_author_last_name: Noureen
      add_author_middle: ''
      add_author_organization: 'Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA'
    - add_author_degree: PhD
      add_author_first_name: 'Ashly '
      add_author_last_name: Hindle
      add_author_middle: ''
      add_author_organization: 'Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA'
    - add_author_degree: MS
      add_author_first_name: Kristyn
      add_author_last_name: McCoy
      add_author_middle: ''
      add_author_organization: 'Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA'
    - add_author_degree: BS
      add_author_first_name: Jonas
      add_author_last_name: Nance
      add_author_middle: ''
      add_author_organization: 'Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA'
    - add_author_degree: BS
      add_author_first_name: Diana
      add_author_last_name: Ixlamati-Nava
      add_author_middle: ''
      add_author_organization: 'Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA'
    - add_author_degree: MD
      add_author_first_name: Mohamad
      add_author_last_name: Al-Rahwan
      add_author_middle: ''
      add_author_organization: 'Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA'
    - add_author_degree: MD
      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'
    - add_author_degree: MD
      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'
    - add_author_degree: MD
      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: MD
      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: MD
      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: MD
      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: 'MD PhD'
      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: 'Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA'
    - add_author_degree: 'MD PhD'
      add_author_first_name: 'C Patrick'
      add_author_last_name: Reynolds
      add_author_middle: ''
      add_author_organization: 'Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA'
  abstract: |+
    Patient-derived models of neuroblastoma are essential for defining resistance mechanisms and for preclinical studies seeking to reverse drug resistance.  We have established and characterized patient derived xenografts (PDXs) and patient derived cell lines (PDCLs) from neuroblastoma patients with progressive disease from samples obtained post-mortem (PD-PM).Tumor and blood samples were cultured and/or subcutaneously xenografted into NOD SCIDγ mice. PDCLs and PDXs were validated by STR profiling and confirmed to be free of Epstein–Barr virus and mycoplasma. Whole exome sequencing identified mutations; telomere maintenance mechanisms were assessed using TERT qPCR, C-circle assay, and TERT break-apart FISH. Therapeutic responses were evaluated in subcutaneous xenografts.  PD-PM specimens showed higher xenograft engraftment rates (68%; 21 of 31 specimens, 83% for PD-PM blood specimens) and higher PDCL take rates (54%, 25 of 46 specimens) compared to diagnosis (Dx, 17%) or progressive disease (PD, 11%, P<0.001) specimens. PD-PM PDXs exhibited higher mutation burdens than Dx PDXs (P=0.026), with 33% harboring canonical activating ALK mutations and another 33% having mutations in other RAS-MAPK signaling genes. Among 20 high TERT-expressing PD-PM PDXs, 13 had MYCN amplification; 4 MYCN non-amplified PDXs exhibited TERT rearrangements. One PD-PM PDX was alternative lengthening of telomeres positive. Relative to one Dx and one PD PDXs, duration of response to temozolomide + irinotecan was low in 3 PD-PM PDXs (P<0.001). Thus, PD-PM PDXs activate ALK or RAS-MAPK signaling, manifest high levels of therapy resistance, and provide models to study reversing drug resistance.  These PDXs are freely available from the COG/ALSF 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_: patrick.reynolds@ttuhsc.edu
  institution_: 'Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA'
  presenting_author_: 'C Patrick Reynolds'