Poster Presentation Advances in Neuroblastoma Research Congress 2016

Cell lines (CLs) and patient derived xenografts (PDXs) established from post-mortem neuroblastoma samples display heterogeneity in sensitivity to chemotherapeutic agents commonly utilized in the treatment of high-risk neuroblastoma patients. (#293)

Michael M Song 1 , David P Woodburn 1 , Heather L Davidson 1 , Heather A Hall 1 , Kerri White 1 , Kristyn E McCoy 1 , Jonas A Nance 1 , Rachel L Blaydes 1 , Wan Hsi Chen 1 , Ashly Hindle 1 , Balakrishna Koneru 1 , Monish R Makena 1 , Michael D Hogarty 2 , John M Maris 2 , Yael P Mosse 2 , Araz Marachelian 3 , Robert C Seeger 3 , Suzanne Meredith 4 , Stephen S Roberts 5 , Steven G Dubois 6 , Mohamad M Al-Rahawan 7 , Naomi J Winick 8 , W. Thomas Cash 9 , Meredith S Irwin 10 , Jennifer M Pearce 11 , Chibuzo C O'Suoji 12 , Min H Kang 1 , Patrick Reynolds 1
  1. Texas Tech University Health Sciences Center School of Medicine Cancer Center, Lubbock, Texas, United States
  2. Children's Hospital of Philadelphia (CHOP) Cancer Center, Philadelphia, Pennsylvania, United States
  3. Children's Hospital Los Angeles (CHLA), Los Angeles, California, United States
  4. Dana-Farber Cancer Institute and Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, United States
  5. Memorial Sloan Kettering Cancer Center, New York, United States
  6. Department of Pediatrics - Division of Hematology/Oncology, University of California San Francisco School of Medicine, San Francisco, California, United States
  7. St. Jude Children's Research Hospital Midwest Affiliate Clinic, Peoria, Illinois, United States
  8. Department of Pediatrics - Division of Hematology Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
  9. Children's Hospital of Atlanta, Atlanta, Georgia, United States
  10. The Hospital for Sick Children, Toronto, Ontario, Canada
  11. Albany Medical Center, Albany, New York, United States
  12. West Virginia University - Charleston School of Medicine, Charleston, West Virginia, United States

Introduction: Cancer cell lines (CLs) and patient-derived xenografts (PDXs) are essential for biological and preclinical therapeutic studies.  CLs and PDXs can be established from post-mortem neuroblastoma (NB) samples.  We assessed the activity of a chemotherapy regimen commonly used for re-induction chemotherapy in 72 NB CLs and 9 xenograft models which were established from either pre-treatment (DX) or post-mortem (PM) samples.


Methods: STR-validated, tyrosine hydroxylase-positive, EBV-negative continuous NB CLs (47 DX, 25 PM) were profiled for 4-hydroperoxy-cyclophosphamide (4-HC, 0-30µM) and topotecan (TOPO, 0-1µM) cytotoxicity with the DIMSCAN assay.  Response of 9 SQ xenograft models (7 PDXs, 2 CL-xenografts (CLX)) to cyclophosphamide (CYCLO) + topotecan was assessed in nu/nu mice. Cytotoxicity in vitro of 4-HC+TOPO was assessed for the PDX models and their matching cell lines.


Results: To date, 25 validated, continuous CLs and 10 PDXs have been established from 40 NB PM samples:  65% blood (50-200mL), 12.5% bone marrow, and 22.5% tumor; 25 of 40 placed in culture (63%) generated a CL, 10 of 16 xenografted (63%) generated a PDX.  Success with PM samples was higher than observed for 1838 pre-treatment (CLs=6.6%, PDXs=9.7%) and 246 progressive disease (CLs=17.1%, PDXs=2.9%) samples.   Both DX and PM models demonstrated heterogeneity in response to 4-HC+TOPO in vitro and CYCLO+TOPO in vivo; some were highly resistant while others highly sensitive. Complete tumor responses after 1-2 cycles were observed in 1 of 2 DX and 2 of 4 PM PDXs.  PDXs and CLs established from the same samples demonstrated comparable responses in vitro and in vivo.


Conclusion: CLs and PDXs are readily established post-mortem from heavily pre-treated patients and demonstrated marked heterogeneity in response to CYCLO (4-HC) + TOPO in vitro and in vivo.  PM NB models will enable delineation of molecular mechanisms of drug resistance, provide ideal models for testing new agents, and are available at