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

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::
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:: {Empty}
Authors::
1. First Name: Balakrishna
   Last Name: Koneru
   Degree(s): PhD
   Organization: Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA
2. First Name: Nighat 
   Last Name: Noureen
   Degree(s): PhD
   Organization: Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA
3. First Name: Ashly 
   Last Name: Hindle
   Degree(s): PhD
   Organization: Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA
4. First Name: Kristyn
   Last Name: McCoy
   Degree(s): MS
   Organization: Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA
5. First Name: Jonas
   Last Name: Nance
   Degree(s): BS
   Organization: Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA
6. First Name: Diana
   Last Name: Ixlamati-Nava
   Degree(s): BS
   Organization: Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA
7. First Name: Mohamad
   Last Name: Al-Rahwan
   Degree(s): MD
   Organization: Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA
8. First Name: Yael
   Middle Initial: P
   Last Name: Mosse
   Degree(s): MD
   Organization: Division of Oncology and Center for Childhood Cancer Research; Children’s Hospital of Philadelphia, Philadelphia, PA USA
9. First Name: John
   Middle Initial: M
   Last Name: Maris
   Degree(s): MD
   Organization: Division of Oncology and Center for Childhood Cancer Research; Children’s Hospital of Philadelphia, Philadelphia, PA USA
10. First Name: Shahab
    Last Name: Asgharzadeh
    Degree(s): MD
    Organization: Children's Hospital of Los Angeles, Los Angeles, CA, USA
11. First Name: Araz
    Last Name: Marachelian
    Degree(s): MD
    Organization: Children's Hospital of Los Angeles, Los Angeles, CA, USA
12. First Name: Meredith
    Middle Initial: S
    Last Name: Irwin
    Degree(s): MD
    Organization: Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada
13. First Name: Suzanne
    Last Name: Shusterman
    Degree(s): MD
    Organization: Dana-Farber/Harvard Cancer Center, Boston, MA, USA  
14. First Name: Stephen
    Middle Initial: S
    Last Name: Roberts
    Degree(s): MD PhD
    Organization: Oregon Health and Science University, Portland, OR USA
15. First Name: Min
    Middle Initial: H
    Last Name: Kang
    Degree(s): PharmD
    Organization: Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA
16. First Name: C Patrick
    Last Name: Reynolds
    Degree(s): MD PhD
    Organization: Texas Tech University Health Sciences Center School of Medicine Lubbock, TX, USA

Presenting Author:: C Patrick Reynolds
Institution:: Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA
Email Address:: patrick.reynolds@ttuhsc.edu