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Opinion

Too many targets, not enough patients: rethinking neuroblastoma clinical trials

Abstract

Neuroblastoma is a rare solid tumour of infancy and early childhood with a disproportionate contribution to paediatric cancer mortality and morbidity. Combination chemotherapy, radiation therapy and immunotherapy remains the standard approach to treat high-risk disease, with few recurrent, actionable genetic aberrations identified at diagnosis. However, recent studies indicate that actionable aberrations are far more common in relapsed neuroblastoma, possibly as a result of clonal expansion. In addition, although the major validated disease driver, MYCN, is not currently directly targetable, multiple promising approaches to target MYCN indirectly are in development. We propose that clinical trial design needs to be rethought in order to meet the challenge of providing rigorous, evidence-based assessment of these new approaches within a fairly small patient population and that experimental therapies need to be assessed at diagnosis in very-high-risk patients rather than in relapsed and refractory patients.

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Fig. 1: Recurrent aberrations in neuroblastoma, their associated pathways and targeted agents matched to these aberrations.
Fig. 2: Multi-arm multi-stage or adaptive trial design for neuroblastoma.

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References

  1. Marshall, G. M. et al. The prenatal origins of cancer. Nat. Rev. Cancer 14, 277–289 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Matthay, K. K. et al. Neuroblastoma. Nat. Rev. Dis. Primers 2, 16078 (2016).

    Article  PubMed  Google Scholar 

  3. Howlader, N. et al. SEER Cancer Statistics Review, 1975–2014. (National Cancer Institute, Bethesda, MD, 2017).

    Google Scholar 

  4. Pinto, N. R. et al. Advances in risk classification and treatment strategies for neuroblastoma. J. Clin. Oncol. 33, 3008–3017 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Eleveld, T. F. et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat. Genet. 47, 864–871 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Schramm, A. et al. Mutational dynamics between primary and relapse neuroblastomas. Nat. Genet. 47, 872–877 (2015).

    Article  PubMed  CAS  Google Scholar 

  7. Abbasi, M. R. et al. Impact of disseminated neuroblastoma cells on the identification of the relapse-seeding clone. Clin. Cancer Res. 23, 4224–4232 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Orentas, R. J. & Mackall, C. L. Emerging immunotherapies for cancer and their potential for application in pediatric oncology. Crit. Rev. Oncog. 20, 315–327 (2015).

    Article  PubMed  Google Scholar 

  9. Campbell, K. et al. Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: a report from the Children’s Oncology Group. Cancer 123, 4224–4235 (2017).

    Article  PubMed  CAS  Google Scholar 

  10. Cohn, S. L. et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J. Clin. Oncol. 27, 289–297 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Brodeur, G. M., Seeger, R. C., Schwab, M., Varmus, H. E. & Bishop, J. M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224, 1121–1124 (1984).

    Article  PubMed  CAS  Google Scholar 

  12. Seeger, R. C. et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N. Engl. J. Med. 313, 1111–1116 (1985).

    Article  PubMed  CAS  Google Scholar 

  13. Weiss, W., Aldape, K., Mohapatra, G., Feuerstein, B. & Bishop, J. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 16, 2985–2995 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Attiyeh, E. F. et al. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N. Engl. J. Med. 353, 2243–2253 (2005).

    Article  PubMed  CAS  Google Scholar 

  15. Bown, N. et al. Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N. Engl. J. Med. 340, 1954–1961 (1999).

    Article  PubMed  CAS  Google Scholar 

  16. Peifer, M. et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 526, 700–704 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Valentijn, L. J. et al. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat. Genet. 47, 1411–1414 (2015).

    Article  PubMed  CAS  Google Scholar 

  18. Cheung, N. K. et al. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA 307, 1062–1071 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Heaphy, C. M. et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science 333, 425 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Hertwig, F., Peifer, M. & Fischer, M. Telomere maintenance is pivotal for high-risk neuroblastoma. Cell Cycle 15, 311–312 (2016).

    Article  PubMed  CAS  Google Scholar 

  21. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Pugh, T. J. et al. The genetic landscape of high-risk neuroblastoma. Nat. Genet. 45, 279–284 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Molenaar, J. J. et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483, 589–593 (2012).

    Article  PubMed  CAS  Google Scholar 

  24. Chmielecki, J. et al. Genomic profiling of a large set of diverse pediatric cancers identifies known and novel mutations across tumor spectra. Cancer Res. 77, 509–519 (2017).

    Article  PubMed  CAS  Google Scholar 

  25. Schleiermacher, G. et al. Emergence of new ALK mutations at relapse of neuroblastoma. J. Clin. Oncol. 32, 2727–2734 (2014).

    Article  PubMed  CAS  Google Scholar 

  26. Kapoor, A. et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158, 185–197 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Padovan-Merhar, O. M. et al. Enrichment of targetable mutations in the relapsed neuroblastoma genome. PLoS Genet. 12, e1006501 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Iwahara, T. et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 14, 439–449 (1997).

    Article  PubMed  CAS  Google Scholar 

  29. Morris, S. W. et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 263, 1281–1284 (1994).

    Article  PubMed  CAS  Google Scholar 

  30. Hallberg, B. & Palmer, R. H. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat. Rev. Cancer 13, 685–700 (2013).

    Article  PubMed  CAS  Google Scholar 

  31. Sebolt-Leopold, J. S. & Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat. Rev. Cancer 4, 937–947 (2004).

    Article  PubMed  CAS  Google Scholar 

  32. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501 (2002).

    Article  PubMed  CAS  Google Scholar 

  33. Gustafson, W. C. & Weiss, W. A. Myc proteins as therapeutic targets. Oncogene 29, 1249–1259 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Janoueix-Lerosey, I. et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455, 967–970 (2008).

    Article  PubMed  CAS  Google Scholar 

  35. Mosse, Y. P. et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455, 930–935 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Berry, T. et al. The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell 22, 117–130 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Heukamp, L. C. et al. Targeted expression of mutated ALK induces neuroblastoma in transgenic mice. Sci. Transl Med. 4, 141ra91 (2012).

    Article  PubMed  CAS  Google Scholar 

  38. Schulte, J. H. et al. MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells. Oncogene 32, 1059–1065 (2013).

    Article  PubMed  CAS  Google Scholar 

  39. Bresler, S. C. et al. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 26, 682–694 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Bresler, S. C. et al. Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci. Transl Med. 3, 108ra114 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Mosse, Y. P., Wood, A. & Maris, J. M. Inhibition of ALK signaling for cancer therapy. Clin. Cancer Res. 15, 5609–5614 (2009).

    Article  PubMed  CAS  Google Scholar 

  42. Mosse, Y. P. et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 14, 472–480 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Sasaki, T. et al. The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res. 70, 10038–10043 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Krytska, K. et al. Crizotinib synergizes with chemotherapy in preclinical models of neuroblastoma. Clin. Cancer Res. 22, 948–960 (2016).

    Article  PubMed  CAS  Google Scholar 

  45. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01742286 (2017).

  46. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02650401 (2017).

  47. Infarinato, N. R. et al. The ALK/ROS1 inhibitor PF-06463922 overcomes primary resistance to crizotinib in ALK-driven neuroblastoma. Cancer Discov. 6, 96–107 (2016).

    Article  PubMed  CAS  Google Scholar 

  48. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03107988 (2017).

  49. Sakamoto, H. et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 19, 679–690 (2011).

    Article  PubMed  CAS  Google Scholar 

  50. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01606878 (2017).

  51. Wood, A. et al. Dual ALK and CDK4/6 inhibition demonstrates on-target synergy against neuroblastoma. Clin. Cancer Res. 23, 2856–2868 (2017).

    Article  PubMed  CAS  Google Scholar 

  52. Moore, N. F. et al. Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma. Oncotarget 5, 8737–8749 (2014).

    PubMed  PubMed Central  Google Scholar 

  53. Cazes, A. et al. Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma. Oncotarget 5, 2688–2702 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lambertz, I. et al. Upregulation of MAPK negative feedback regulators and RET in mutant ALK neuroblastoma: implications for targeted treatment. Clin. Cancer Res. 21, 3327–3339 (2015).

    Article  PubMed  CAS  Google Scholar 

  55. Tanaka, T. et al. MEK inhibitors as a novel therapy for neuroblastoma: their in vitro effects and predicting their efficacy. J. Pediatr. Surg. 51, 2074–2079 (2016).

    Article  PubMed  Google Scholar 

  56. Woodfield, S. E., Zhang, L., Scorsone, K. A., Liu, Y. & Zage, P. E. Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression. BMC Cancer 16, 172 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Holzel, M. et al. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell 142, 218–229 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. He, S. et al. Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain. eLife 5, e14713 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Kakodkar, N. C. et al. Sorafenib inhibits neuroblastoma cell proliferation and signaling, blocks angiogenesis, and impairs tumor growth. Pediatr. Blood Cancer 59, 642–647 (2012).

    Article  PubMed  Google Scholar 

  60. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02298348 (2017).

  61. Bautista, F. et al. Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas. Pediatr. Blood Cancer 61, 1101–1103 (2014).

    Article  PubMed  CAS  Google Scholar 

  62. Chesler, L. et al. Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Cancer Res. 66, 8139–8146 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT00776867 (2017).

  64. Kushner, B. H. et al. A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: long-term progression-free survival of patients with resistant neuroblastoma. Int. J. Cancer 140, 480–484 (2017).

    Article  PubMed  CAS  Google Scholar 

  65. Becher, O. J. et al. A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors. Pediatr. Blood Cancer 64, e26409 (2017).

    Article  CAS  Google Scholar 

  66. Kiessling, M. K. et al. Targeting the mTOR complex by everolimus in NRAS mutant neuroblastoma. PLoS ONE 11, e0147682 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Huang, M. & Weiss, W. A. Neuroblastoma and MYCN. Cold Spring Harb. Perspect. Med. 3, a014415 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Mugrauer, G., Alt, F. W. & Ekblom, P. N-Myc proto-oncogene expression during organogenesis in the developing mouse as revealed by in situ hybridization. J. Cell Biol. 107, 1325–1335 (1988).

    Article  PubMed  CAS  Google Scholar 

  69. Burkhart, C. A. et al. Effects of MYCN antisense oligonucleotide administration on tumorigenesis in a murine model of neuroblastoma. J. Natl Cancer Inst. 95, 1394–1403 (2003).

    Article  PubMed  Google Scholar 

  70. Fletcher, S. & Prochownik, E. V. Small-molecule inhibitors of the Myc oncoprotein. Biochim. Biophys. Acta 1849, 525–543 (2015).

    Article  PubMed  CAS  Google Scholar 

  71. Puissant, A. et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 3, 308–323 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Henssen, A. et al. Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition. Clin. Cancer Res. 22, 2470–2481 (2016).

    Article  PubMed  CAS  Google Scholar 

  73. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01713582 (2017).

  74. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02259114 (2017).

  75. Nilson, K. A. et al. THZ1 reveals roles for Cdk7 in co-transcriptional capping and pausing. Mol. Cell 59, 576–587 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Chipumuro, E. et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159, 1126–1139 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Zeid, R. et al. Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma. Nat. Genet. https://doi.org/10.1038/s41588-018-0044-9 (2018).

  78. Garcia, H. et al. Facilitates chromatin transcription complex is an “accelerator” of tumor transformation and potential marker and target of aggressive cancers. Cell Rep. 4, 159–173 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Carter, D. R. et al. Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma. Sci. Transl Med. 7, 312ra176 (2015).

    Article  PubMed  CAS  Google Scholar 

  80. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01905228 (2017).

  81. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02931110 (2017).

  82. Henrich, K. O. et al. Integrative genome-scale analysis identifies epigenetic mechanisms of transcriptional deregulation in unfavorable neuroblastomas. Cancer Res. 76, 5523–5537 (2016).

    Article  PubMed  CAS  Google Scholar 

  83. Waldeck, K. et al. Long term, continuous exposure to panobinostat induces terminal differentiation and long term survival in the TH-MYCN neuroblastoma mouse model. Int. J. Cancer 139, 194–204 (2016).

    Article  PubMed  CAS  Google Scholar 

  84. Otto, T. et al. Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell 15, 67–78 (2009).

    Article  PubMed  CAS  Google Scholar 

  85. Mosse, Y. P. et al. Pediatric phase I trial and pharmacokinetic study of MLN8237, an investigational oral selective small-molecule inhibitor of Aurora kinase A: a Children’s Oncology Group Phase I Consortium study. Clin. Cancer Res. 18, 6058–6064 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. DuBois, S. G. et al. Phase I study of the Aurora A kinase inhibitor alisertib in combination with irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma: a NANT (New Approaches to Neuroblastoma Therapy) trial. J. Clin. Oncol. 34, 1368–1375 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Gustafson, W. C. et al. Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell 26, 414–427 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Richards, M. W. et al. Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. Proc. Natl Acad. Sci. USA 113, 13726–13731 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Molenaar, J. J. et al. Copy number defects of G1-cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis. Genes Chromosomes Cancer 51, 10–19 (2012).

    Article  PubMed  CAS  Google Scholar 

  90. Rader, J. et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin. Cancer Res. 19, 6173–6182 (2013).

    Article  PubMed  CAS  Google Scholar 

  91. Geoerger, B. et al. A phase I study of the CDK4/6 inhibitor ribociclib (LEE011) in pediatric patients with malignant rhabdoid tumors, neuroblastoma, and other solid tumors. Clin. Cancer Res. 23, 2433–2441 (2017).

    Article  PubMed  CAS  Google Scholar 

  92. Hart, L. S. et al. Preclinical therapeutic synergy of MEK1/2 and CDK4/6 inhibition in neuroblastoma. Clin. Cancer Res. 23, 1785–1796 (2017).

    Article  PubMed  CAS  Google Scholar 

  93. Gorlick, R. et al. Initial testing (stage 1) of the Polo-like kinase inhibitor volasertib (BI 6727), by the Pediatric Preclinical Testing Program. Pediatr. Blood Cancer 61, 158–164 (2014).

    Article  PubMed  CAS  Google Scholar 

  94. Maris, J. M. et al. Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP). Pediatr. Blood Cancer 55, 26–34 (2010).

    PubMed  PubMed Central  Google Scholar 

  95. Lowery, C. D. et al. The Checkpoint kinase 1 inhibitor prexasertib induces regression of preclinical models of human neuroblastoma. Clin. Cancer Res. 23, 4354–4363 (2017).

    Article  PubMed  CAS  Google Scholar 

  96. Dolman, M. E. et al. Cyclin-dependent kinase inhibitor AT7519 as a potential drug for MYCN-dependent neuroblastoma. Clin. Cancer Res. 21, 5100–5109 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Bello-Fernandez, C., Packham, G. & Cleveland, J. L. The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc. Natl Acad. Sci. USA 90, 7804–7808 (1993).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Hogarty, M. D. et al. ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma. Cancer Res. 68, 9735–9745 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Evageliou, N. F. et al. Polyamine Antagonist Therapies Inhibit Neuroblastoma Initiation and Progression. Clin. Cancer Res. 22, 4391–4404 (2016).

    Article  PubMed  CAS  Google Scholar 

  100. Saulnier Sholler, G. L. et al. A phase I trial of DFMO targeting polyamine addiction in patients with relapsed/refractory neuroblastoma. PLoS ONE 10, e0127246 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02030964 (2017).

  102. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02139397 (2017).

  103. Carr-Wilkinson, J. et al. High frequency of p53/MDM2/p14ARF pathway abnormalities in relapsed neuroblastoma. Clin. Cancer Res. 16, 1108–1118 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Van Maerken, T. et al. Antitumor activity of the selective MDM2 antagonist nutlin-3 against chemoresistant neuroblastoma with wild-type p53. J. Natl Cancer Inst. 101, 1562–1574 (2009).

    Article  PubMed  CAS  Google Scholar 

  105. Lakoma, A. et al. The MDM2 small-molecule inhibitor RG7388 leads to potent tumor inhibition in p53 wild-type neuroblastoma. Cell Death Discov. 1, 15026 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Veschi, V. et al. Epigenetic siRNA and Chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell 31, 50–63 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Goldsmith, K. C. et al. BH3 response profiles from neuroblastoma mitochondria predict activity of small molecule Bcl-2 family antagonists. Cell Death Differ. 17, 872–882 (2010).

    Article  PubMed  CAS  Google Scholar 

  108. Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202–208 (2013).

    Article  PubMed  CAS  Google Scholar 

  109. Kotschy, A. et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538, 477–482 (2016).

    Article  PubMed  CAS  Google Scholar 

  110. Tanos, R., Karmali, D., Nalluri, S. & Goldsmith, K. C. Select Bcl-2 antagonism restores chemotherapy sensitivity in high-risk neuroblastoma. BMC Cancer 16, 97 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Bate-Eya, L. T. et al. High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition. Oncotarget 7, 27946–27958 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Ham, J. et al. Exploitation of the apoptosis-primed state of MYCN-amplified neuroblastoma to develop a potent and specific targeted therapy combination. Cancer Cell 29, 159–172 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Garaventa, A. et al. Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry. Eur. J. Cancer 45, 2835–2842 (2009).

    Article  PubMed  Google Scholar 

  114. London, W. B. et al. Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J. Clin. Oncol. 29, 3286–3292 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Moreno, L. et al. Outcome of children with relapsed or refractory neuroblastoma: A meta-analysis of ITCC/SIOPEN European phase II clinical trials. Pediatr. Blood Cancer 64, 25–31 (2017).

    Article  PubMed  CAS  Google Scholar 

  116. London, W. B. et al. Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children’s Oncology Group early-phase trials. Cancer 123, 4914–4923 (2017).

    Article  PubMed  CAS  Google Scholar 

  117. Ladenstein, R. et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 18, 500–514 (2017).

    Article  PubMed  CAS  Google Scholar 

  118. Kreissman, S. G. et al. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 14, 999–1008 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Mosse, Y. P. et al. Neuroblastoma in older children, adolescents and young adults: a report from the International Neuroblastoma Risk Group project. Pediatr. Blood Cancer 61, 627–635 (2014).

    Article  PubMed  Google Scholar 

  120. Morgenstern, D. A. et al. Prognostic significance of pattern and burden of metastatic disease in patients with stage 4 neuroblastoma: A study from the International Neuroblastoma Risk Group database. Eur. J. Cancer 65, 1–10 (2016).

    Article  PubMed  Google Scholar 

  121. Decarolis, B. et al. Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study. J. Clin. Oncol. 31, 944–951 (2013).

    Article  PubMed  CAS  Google Scholar 

  122. Ady, N. et al. A new 123I-MIBG whole body scan scoring method — application to the prediction of the response of metastases to induction chemotherapy in stage IV neuroblastoma. Eur. J. Cancer 31A, 256–261 (1995).

    Article  PubMed  CAS  Google Scholar 

  123. Matthay, K. K. et al. Correlation of early metastatic response by 123I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J. Clin. Oncol. 21, 2486–2491 (2003).

    Article  PubMed  Google Scholar 

  124. Katzenstein, H. M. et al. Scintigraphic response by 123I-metaiodobenzylguanidine scan correlates with event-free survival in high-risk neuroblastoma. J. Clin. Oncol. 22, 3909–3915 (2004).

    Article  PubMed  Google Scholar 

  125. Schmidt, M., Simon, T., Hero, B., Schicha, H. & Berthold, F. The prognostic impact of functional imaging with (123)I-mIBG in patients with stage 4 neuroblastoma > 1 year of age on a high-risk treatment protocol: results of the German Neuroblastoma Trial NB97. Eur. J. Cancer 44, 1552–1558 (2008).

    Article  PubMed  Google Scholar 

  126. Yanik, G. A. et al. Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children’s oncology group. J. Nucl. Med. 54, 541–548 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Ladenstein, R. et al. Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials. Eur. J. Nucl. Med. Mol. Imag. 45, 292–305 (2018).

    Article  Google Scholar 

  128. Yanik, G. A. et al. Validation of post-induction Curie scores in high risk neuroblastoma. A Children’s Oncology Group (COG) and SIOPEN group report on SIOPEN/HR-NBL1. J. Nucl. Med. 59, 502–508 (2018).

  129. Burchill, S. A. et al. Circulating neuroblastoma cells detected by reverse transcriptase polymerase chain reaction for tyrosine hydroxylase mRNA are an independent poor prognostic indicator in stage 4 neuroblastoma in children over 1 year. J. Clin. Oncol. 19, 1795–1801 (2001).

    Article  PubMed  CAS  Google Scholar 

  130. Seeger, R. C. et al. Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children’s Cancer Group Study. J. Clin. Oncol. 18, 4067–4076 (2000).

    Article  PubMed  CAS  Google Scholar 

  131. Viprey, V. F. et al. Neuroblastoma mRNAs predict outcome in children with stage 4 neuroblastoma: a European HR-NBL1/SIOPEN study. J. Clin. Oncol. 32, 1074–1083 (2014).

    Article  PubMed  CAS  Google Scholar 

  132. Vermeulen, J. et al. Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study. Lancet Oncol. 10, 663–671 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Oberthuer, A. et al. Prognostic impact of gene expression-based classification for neuroblastoma. J. Clin. Oncol. 28, 3506–3515 (2010).

    Article  PubMed  Google Scholar 

  134. De Preter, K. et al. Accurate outcome prediction in neuroblastoma across independent data sets using a multigene signature. Clin. Cancer Res. 16, 1532–1541 (2010).

    Article  PubMed  CAS  Google Scholar 

  135. Stricker, T. P. et al. Validation of a prognostic multi-gene signature in high-risk neuroblastoma using the high throughput digital NanoString nCounter system. Mol. Oncol. 8, 669–678 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Matthay, K. K. et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N. Engl. J. Med. 341, 1165–1173 (1999).

    Article  PubMed  CAS  Google Scholar 

  137. Park, J. R. et al. Outcome of high-risk stage 3 neuroblastoma with myeloablative therapy and 13-cis-retinoic acid: a report from the Children’s Oncology Group. Pediatr. Blood Cancer 52, 44–50 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  138. DuBois, S. G. et al. MIBG avidity correlates with clinical features, tumor biology, and outcomes in neuroblastoma: a report from the Children’s Oncology Group. Pediatr. Blood Cancer 64, e26545 (2017).

    Article  CAS  Google Scholar 

  139. Morgenstern, D. A. et al. Metastatic neuroblastoma confined to distant lymph nodes (stage 4N) predicts outcome in patients with stage 4 disease: a study from the International Neuroblastoma Risk Group Database. J. Clin. Oncol. 32, 1228–1235 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Yu, A. L. et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl. J. Med. 363, 1324–1334 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Park, J. R. et al. in Advances in Neuroblastoma Research Congress 2016 (Cairns, Qld, Australia, 2016).

  142. Freidlin, B., Korn, E. L., Gray, R. & Martin, A. Multi-arm clinical trials of new agents: some design considerations. Clin. Cancer Res. 14, 4368–4371 (2008).

    Article  PubMed  CAS  Google Scholar 

  143. Rugo, H. S. et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N. Engl. J. Med. 375, 23–34 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Castleberry, R. P. et al. Phase II investigational window using carboplatin, iproplatin, ifosfamide, and epirubicin in children with untreated disseminated neuroblastoma: a Pediatric Oncology Group study. J. Clin. Oncol. 12, 1616–1620 (1994).

    Article  PubMed  CAS  Google Scholar 

  145. Zage, P. E. et al. Outcomes of the POG 9340/9341/9342 trials for children with high-risk neuroblastoma: a report from the Children’s Oncology Group. Pediatr. Blood Cancer 51, 747–753 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Mody, R. et al. Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol. 18, 946–957 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Bagatell, R. et al. Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children’s Oncology Group study. J. Clin. Oncol. 29, 208–213 (2011).

    Article  PubMed  CAS  Google Scholar 

  148. Sposto, R. & Stram, D. O. A strategic view of randomized trial design in low-incidence paediatric cancer. Stat. Med. 18, 1183–1197 (1999).

    Article  PubMed  CAS  Google Scholar 

  149. Deley, M. C., Ballman, K. V., Marandet, J. & Sargent, D. Taking the long view: how to design a series of Phase III trials to maximize cumulative therapeutic benefit. Clin. Trials 9, 283–292 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Bayar, M. A., Le Teuff, G., Michiels, S., Sargent, D. J. & Le Deley, M. C. New insights into the evaluation of randomized controlled trials for rare diseases over a long-term research horizon: a simulation study. Stat. Med. 35, 3245–3258 (2016).

    Article  PubMed  Google Scholar 

  151. Devidas, M. & Anderson, J. R. Considerations in the design of clinical trials for pediatric acute lymphoblastic leukemia. Clin. Investig. 3, 849–858 (2013).

    Article  CAS  Google Scholar 

  152. Vassal, G. et al. New drugs for children and adolescents with cancer: the need for novel development pathways. Lancet Oncol. 14, e117–e124 (2013).

    Article  PubMed  Google Scholar 

  153. Pearson, A. D. J. et al. From class waivers to precision medicine in paediatric oncology. Lancet Oncol. 18, e394–e404 (2017).

    Article  PubMed  Google Scholar 

  154. Boubaker, A. & Bischof Delaloye, A. MIBG scintigraphy for the diagnosis and follow-up of children with neuroblastoma. Q. J. Nucl. Med. Mol. Imag. 52, 388–402 (2008).

    CAS  Google Scholar 

  155. Boeva, V. et al. Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries. Nat. Genet. 49, 1408–1413 (2017).

    Article  PubMed  CAS  Google Scholar 

  156. Bettegowda, C. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl Med. 6, 224ra24 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Wan, J. C. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17, 223–238 (2017).

    Article  PubMed  CAS  Google Scholar 

  158. Murtaza, M. et al. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. Nat. Commun. 6, 8760 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Chicard, M. et al. Genomic copy number profiling using circulating free tumor DNA highlights heterogeneity in neuroblastoma. Clin. Cancer Res. 22, 5564–5573 (2016).

    Article  PubMed  CAS  Google Scholar 

  160. Combaret, V. et al. Detection of tumor ALK status in neuroblastoma patients using peripheral blood. Cancer Med. 4, 540–550 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Kurihara, S. et al. Circulating free DNA as non-invasive diagnostic biomarker for childhood solid tumors. J. Pediatr. Surg. 50, 2094–2097 (2015).

    Article  PubMed  Google Scholar 

  162. Houghton, P. J. et al. The pediatric preclinical testing program: description of models and early testing results. Pediatr. Blood Cancer 49, 928–940 (2007).

    Article  PubMed  Google Scholar 

  163. Townsend, E. C. et al. The public repository of xenografts enables discovery and randomized phase II-like trials in mice. Cancer Cell 29, 574–586 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors regret that, because of space limitations, they could not cite all original research articles and related references on this topic. Research in the authors’ laboratories is supported by National Health and Medical Research Council (NHMRC) Program Grant APP1016699, Development Grant APP1136278, Project Grants APP1125036 and 1085411 and Cancer Institute New South Wales (NSW) Translational Program Grant 10/TPG/1-03.

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M.D.N., G.M.M. and M.H. substantially contributed to discussions of content and reviewed and edited the manuscript before submission. J.I.F., D.S.Z. and T.N.T. researched data for the article, substantially contributed to discussions of content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Murray D. Norris.

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M.D.N. and M.H. own stock in Cleveland BioLabs, which is entitled to a portion of the royalties for sale of the Incuron product CBL0137. The other authors declare that they have no competing interests.

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Related links

NCI Patient-Derived Models Repository: https://pdmr.cancer.gov/

Glossary

Children’s Oncology Group

(COG). A childhood and adolescent cancer clinical trial consortium based in North America.

European International Society of Paediatric Oncology Neuroblastoma Group

(SIOPEN). A neuroblastoma clinical trials consortium based in Europe.

GD2 immunotherapy

An anti-neuroblastoma cancer immunotherapy that uses monoclonal antibodies targeting GD2 (for example, dinutuximab), either alone or in conjunction with interleukin-2 and/or granulocyte–macrophage colony-stimulating factor. GD2 is a tumour-associated disialoganglioside found on the surface of neuroblastoma cells.

High-dose therapy–myeloablative transplant

A treatment regimen involving very-high-dose chemotherapy with autologous stem cell transplantation that is used to eradicate residual neuroblastoma following induction chemotherapy.

Innovative Therapies for Children with Cancer

(ITCC). An early-phase clinical trial consortium for paediatric and adolescent cancers that is based in Europe.

Metaiodobenzylguanidine therapy

(MIBG therapy). Targeted radiation therapy using MIBG conjugated to iodinated radionuclides such as 131 I-MIBG.

Metastatic response

A measurable, objective response to therapy at metastatic sites.

MIBG scintigraphy

An imaging technique using metaiodobenzylguanidine (MIBG), which is a noradrenaline precursor that is selectively taken up by neuroendocrine cells via the noradrenaline transporter receptor; when radiolabelled, this uptake can be exploited for functional imaging.

MIBG non-avid disease

Cases of neuroblastoma (5–10%) with low or absent noradrenaline transporter receptor expression and thus no accumulation of metaiodobenzylguanidine (MIBG).

Type 1 error rate

The rate at which the null hypothesis is mistakenly rejected; the threshold is commonly set arbitrarily at 0.05 (5%). Relaxing the type 1 error threshold increases the chance of selecting a new treatment even if it is worse than standard of care but allows for smaller, faster trials and increased progress on average over time, resulting in better treatments and outcomes. As proposed new treatments are rarely worse than the standard of care, P values of 0.05 and 0.15 have only a 3% and a 7% chance, respectively, of selecting a worse treatment.

Window-of-opportunity design

A trial design in which patients receive one or more novel antitumour agents between their cancer diagnosis and standard-of-care therapy. Tumour sampling is undertaken before and after therapy for translational research.

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Fletcher, J.I., Ziegler, D.S., Trahair, T.N. et al. Too many targets, not enough patients: rethinking neuroblastoma clinical trials. Nat Rev Cancer 18, 389–400 (2018). https://doi.org/10.1038/s41568-018-0003-x

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