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

Abstract Submission for Poster Presentation
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Abstract Title:: Neuroblastoma Patient-Derived Xenografts and Cell Lines from Postmortem Blood as Models to Understand and Reverse Therapy Resistance
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).

Authors::
1. First Name: Balakrishna
   Last Name: Koneru
   Degree(s): Ph.D
   Organization: Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
2. First Name: Nighat
   Last Name: Noureen
   Degree(s): Ph.D
   Organization: Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
3. First Name: Ashly
   Last Name: Hindle
   Degree(s): Ph.D
   Organization: Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
4. First Name: Kristyn
   Last Name: Mccoy
   Degree(s): MS
   Organization: Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
5. First Name: Jonas
   Last Name: Nance
   Degree(s): BS
   Organization: Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
6. First Name: Diana
   Last Name: Ixtlamati-Nava
   Degree(s): BS
   Organization: Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
7. First Name: Charles
   Last Name: Zhu
   Degree(s): BS
   Organization: Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
8. First Name: Tenley
   Last Name: Lehman
   Degree(s): BS
   Organization: Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
9. First Name: Mohamad 
   Middle Initial: Al
   Last Name: Rahawan
   Degree(s): M.D.
   Organization: Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
10. First Name: Yael
    Middle Initial: P
    Last Name: Mosse
    Degree(s): M.D.
    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
11. First Name: John
    Middle Initial: M
    Last Name: Maris
    Degree(s): M.D.
    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
12. First Name: Shahab
    Last Name: Asgharzadeh
    Degree(s): M.D.
    Organization: Children's Hospital of Los Angeles, Los Angeles, CA, USA
13. First Name: Araz
    Last Name: Marachelian
    Degree(s): M.D.
    Organization: Children's Hospital of Los Angeles, Los Angeles, CA, USA
14. First Name: Meredith
    Middle Initial: S
    Last Name: Irwin
    Degree(s): M.D.
    Organization: Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada
15. First Name: Suzanne
    Last Name: Shusterman
    Degree(s): M.D.
    Organization: Dana-Farber/Harvard Cancer Center, Boston, MA, USA  
16. First Name: Stephen
    Middle Initial: S
    Last Name: Roberts
    Degree(s): M.D.
    Organization: Oregon Health and Science University, Portland, OR USA
17. First Name: Min
    Middle Initial: H
    Last Name: Kang
    Degree(s): PharmD
    Organization: Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
18. First Name: Patrick
    Last Name: Reynolds
    Degree(s): M.D. Ph.D
    Organization: Pediatric Cancer Research Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA

Presenting Author:: BALAKRISHNA KONERU
Institution:: Texas Tech University Health Sciences Center
Email Address:: balakrishna.koneru@ttuhsc.edu