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Development of treatment strategies for advanced neuroblastoma

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Abstract

Neuroblastoma is the most common cancer in childhood. The majority of patients with neuroblastoma are assigned to the high-risk group based on age at diagnosis, stage, histology, MYCN status, and DNA ploidy. Their prognosis remains unsatisfactory; the 5-year event-free survival (EFS) rate is generally 40 %. During the past 20 years, much effort has been made to reinforce chemotherapy, including the introduction of high-dose chemotherapy with autologous stem cell rescue, resulting in a 5-year EFS rate of around 30 %. Subsequently, maintenance therapy aimed at eradicating residual tumors after induction and consolidation therapies was introduced, consisting of differentiation-inducing agents, retinoids, and immunotherapy using anti-GD2 antibodies combined with cytokines. However, such additional treatment provided benefit to only 10–20 % of patients, while the prognosis of about half the patients remains poor. Currently, novel targeted agents are under development. Among them, anaplastic lymphoma kinase (ALK) inhibitors and aurora kinase A inhibitors are promising. ALK somatic mutation or gene amplification predisposing neuroblastoma development occurs in up to 15 % of neuroblastomas. Crizotinib is a dual-specific inhibitor of ALK/Met and inhibits proliferation of neuroblastoma cells harboring R1275Q-mutated ALK or amplified wild-type ALK, but not cells harboring F1174L. Instead, cells with F1174L are sensitive to another small molecule ALK inhibitor, TAE684. Aurora kinase A plays a pivotal role in centrosome maturation and spindle formation during mitosis. MLN8237 (alisertib) is a small molecule inhibitor of aurora kinase A that is currently in early-phase clinical testing. Future treatment will be individually planned, adapting targeted agents based on personal biological tumor characteristics.

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References

  1. London WB, Castleberry RP, Matthay KK et al (2005) Evidence for age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children’s Oncology Group. J Clin Oncol 23:6459–6465

    Article  PubMed  CAS  Google Scholar 

  2. Cohn SL, Pearson AD, London WB et al (2009) The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 27:289–297

    Article  PubMed  Google Scholar 

  3. Yamamoto K, Harada R, Kikuchi A et al (1998) Spontaneous regression of localized neuroblastoma detected by mass screening. J Clin Oncol 16:1265–1269

    PubMed  CAS  Google Scholar 

  4. Carlsen NL (1990) How frequent is spontaneous remission of neuroblastomas? Implications for screening. Br J Cancer 61:441–446

    Article  PubMed  CAS  Google Scholar 

  5. Cheung NV, Heller G (1991) Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. J Clin Oncol 9:1050–1058

    PubMed  CAS  Google Scholar 

  6. Halperin EC, Cox EB (1986) Radiation therapy in the management of neuroblastoma: the Duke University Medical Center experience 1967–1984. Int J Radiat Oncol Biol Phys 12:1829–1837

    Article  PubMed  CAS  Google Scholar 

  7. Russo C, Cohn SL, Petruzzi MJ et al (1997) Long-term neurologic outcome in children with opsoclonus–myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol 28:284–288

    Article  PubMed  CAS  Google Scholar 

  8. Matthay KK, Villablanca JG, Seeger RC et al (1999) Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 341:1165–1173

    Article  PubMed  CAS  Google Scholar 

  9. Sawaguchi S, Kaneko M, Uchino J et al (1990) Treatment of advanced neuroblastoma with emphasis on intensive induction chemotherapy. A report from the Study Group of Japan. Cancer 66:1879–1887

    Article  PubMed  CAS  Google Scholar 

  10. Pearson AD, Pinkerton CR, Lewis IJ et al (2008) High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol 3:247–256

    Article  Google Scholar 

  11. Vassal G, Doz F, Frappaz D et al (2003) A phase I study of irinotecan as a 3-week schedule in children with refractory or recurrent solid tumors. J Clin Oncol 21:3844–3852

    Article  PubMed  CAS  Google Scholar 

  12. Bomgaars LR, Bernstein M, Krailo M et al (2007) Phase II trial of irinotecan in children with refractory solid tumors: a Children’s Oncology Group Study. J Clin Oncol 25:4622–4627

    Article  PubMed  CAS  Google Scholar 

  13. Vassal G, Giammarile F, Brooks M et al (2008) A phase II study of irinotecan in children with relapsed or refractory neuroblastoma: a European cooperation of the Société Française d’Oncologie Pédiatrique (SFOP) and the United Kingdom Children Cancer Study Group (UKCCSG). Eur J Cancer 44:2453–2460

    Article  PubMed  CAS  Google Scholar 

  14. Saylors RL 3rd, Stine KC, Sullivan J et al (2001) Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19:3463–3469

    PubMed  CAS  Google Scholar 

  15. Kretschmar CS, Kletzel M, Murray K et al (2004) Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: a pediatric oncology group study. J Clin Oncol 22:4119–4126

    Article  PubMed  CAS  Google Scholar 

  16. Park JR, Scott JR, Stewart CF et al (2011) Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children’s Oncology Group study. J Clin Oncol 29:4351–4357

    Article  PubMed  CAS  Google Scholar 

  17. London WB, Frantz CN, Campbell LA et al (2010) Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children’s Oncology Group study. J Clin Oncol 28:3808–3815

    Article  PubMed  CAS  Google Scholar 

  18. Berthold F, Boos J, Burdach S et al (2005) Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol 6:649–658

    Article  PubMed  CAS  Google Scholar 

  19. Ladenstein RL, Poetschger U, Luksch R et al (2011) Busulphan-melphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: results from the HR-NBL1/SIOPEN trial. J Clin Oncol 29(Suppl; abstr 2)

  20. Matthay KK, Reynolds CP, Seeger RC et al (2009) Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a Children’s Oncology Group study. J Clin Oncol 27:1007–1013

    Article  PubMed  CAS  Google Scholar 

  21. Matthay KK, Tan JC, Villablanca JG et al (2006) Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol 24:500–506

    Article  PubMed  CAS  Google Scholar 

  22. Monnereau-Laborde S, Munzer C, Valteau-Couanet D et al (2011) A dose-intensive approach (NB96) for induction therapy utilizing sequential high-dose chemotherapy and stem cell rescue in high-risk neuroblastoma in children over 1 year of age. Pediatr Blood Cancer 57:965–971

    Article  PubMed  Google Scholar 

  23. Pradhan KR, Johnson CS, Vik TA et al (2006) A novel intensive induction therapy for high-risk neuroblastoma utilizing sequential peripheral blood stem cell collection and infusion as hematopoietic support. Pediatr Blood Cancer 46:793–802

    Article  PubMed  Google Scholar 

  24. Qayed M, Chiang KY, Ricketts R et al (2012) Tandem stem cell rescue as consolidation therapy for high-risk neuroblastoma. Pediatr Blood Cancer 58:448–452

    Article  PubMed  Google Scholar 

  25. Kreissman SG, Villablanca JG, Seeger RC et al (2008) A randomized phase III trial of myeloablative autologous peripheral blood stem cell (PBSC) transplant (ASCT) for high-risk neuroblastoma (HR-NB) employing immunomagnetic purged (P) versus unpurged (UP) PBSC: a Children’s Oncology Group study. J Clin Oncol 26(Suppl; abstr 10011)

  26. Sidell N (1982) Retinoic acid-induced growth inhibition and morphologic differentiation of human neuroblastoma cells in vitro. J Natl Cancer Inst 68:589–596

    PubMed  CAS  Google Scholar 

  27. Reynolds CP, Matthay KK, Villablanca JG et al (2003) Retinoid therapy of high-risk neuroblastoma. Cancer Lett 197:185–192

    Article  PubMed  CAS  Google Scholar 

  28. Villablanca JG, London WB, Naranjo A et al (2011) Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: a report from the Children’s Oncology Group. Clin Cancer Res 17:6858–6866

    Article  PubMed  CAS  Google Scholar 

  29. Modak S, Cheung NK (2007) Disialoganglioside directed immunotherapy of neuroblastoma. Cancer Invest 25:67–77

    Article  PubMed  CAS  Google Scholar 

  30. Frost JD, Hank JA, Reaman GH et al (1997) A phase I/IB trial of murine monoclonal anti-GD2 antibody 14.G2a plus interleukin-2 in children with refractory neuroblastoma: a report of the Children’s Cancer Group. Cancer 80:317–333

    Article  PubMed  CAS  Google Scholar 

  31. Yu AL, Uttenreuther-Fischer MM, Huang CS et al (1998) Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. J Clin Oncol 16:2169–2180

    PubMed  CAS  Google Scholar 

  32. Ozkaynak MF, Sondel PM, Krailo MD et al (2000) Phase I study of chimeric human/murine anti-ganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte–macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: a Children’s Cancer Group Study. J Clin Oncol 18:4077–4085

    PubMed  CAS  Google Scholar 

  33. Kushner BH, Kramer K, Cheung NK (2001) Phase II trial of the anti-G(D2) monoclonal antibody 3F8 and granulocyte–macrophage colony-stimulating factor for neuroblastoma. J Clin Oncol 19:4189–4194

    PubMed  CAS  Google Scholar 

  34. Osenga KL, Hank JA, Albertini MR et al (2006) A phase I clinical trial of the hu14.18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the Children’s Oncology Group. Clin Cancer Res 12:1750–1759

    Article  PubMed  CAS  Google Scholar 

  35. Shusterman S, London WB, Gillies SD et al (2010) Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children’s Oncology Group (COG) phase II study. J Clin Oncol 28:4969–4975

    Article  PubMed  CAS  Google Scholar 

  36. Yu AL, Gilman AL, Ozkaynak MF et al (2010) Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363:1324–1334

    Article  PubMed  CAS  Google Scholar 

  37. Kushner BH, Kramer K, Modak S et al (2011) Successful multifold dose escalation of anti-GD2 monoclonal antibody 3F8 in patients with neuroblastoma: a phase I study. J Clin Oncol 29:1168–1174

    Article  PubMed  CAS  Google Scholar 

  38. Cheung NK, Kushner BH, Yeh SD et al (1998) 3F8 monoclonal antibody treatment of patients with stage 4 neuroblastoma: a phase II study. Int J Oncol 12:1299–1306

    PubMed  CAS  Google Scholar 

  39. Mueller BM, Romerdahl CA, Gillies SD et al (1990) Enhancement of antibody-dependent cytotoxicity with a chimeric anti-GD2 antibody. J Immunol 144:1382–1386

    PubMed  CAS  Google Scholar 

  40. Simon T, Hero B, Faldum A et al (2004) Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma. J Clin Oncol 22:3549–3557

    Article  PubMed  CAS  Google Scholar 

  41. Gilman AL, Ozkaynak MF, Matthay KK et al (2009) Phase I study of ch14.18 with granulocyte–macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children’s Oncology Group. J Clin Oncol 27:85–91

    Article  PubMed  CAS  Google Scholar 

  42. Smith MA, Maris JM, Gorlick R et al (2011) Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer. doi:10.1002/pbc.23357

    Google Scholar 

  43. Lock RB, Carol H, Morton CL et al (2012) Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. Pediatr Blood Cancer 58:916–923

    Article  PubMed  Google Scholar 

  44. Smith MA, Maris JM, Lock R et al (2011) Initial testing (stage 1) of the polyamine analog PG11047 by the pediatric preclinical testing program. Pediatr Blood Cancer 57:268–274

    Article  PubMed  Google Scholar 

  45. Kolb EA, Gorlick R, Houghton PJ et al (2008) Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program. Pediatr Blood Cancer 50:1190–1197

    Article  PubMed  Google Scholar 

  46. Houghton PJ, Morton CL, Gorlick R et al (2010) Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 54:921–926

    PubMed  Google Scholar 

  47. Kolb EA, Gorlick R, Lock R et al (2011) Initial testing (stage 1) of the IGF-1 receptor inhibitor BMS-754807 by the pediatric preclinical testing program. Pediatr Blood Cancer 56:595–603

    Article  PubMed  Google Scholar 

  48. Maris JM, Morton CL, Gorlick R et al (2010) Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP). Pediatr Blood Cancer 55:26–34

    PubMed  Google Scholar 

  49. Maris JM, Courtright J, Houghton PJ et al (2008) Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program. Pediatr Blood Cancer 51:42–48

    Article  PubMed  Google Scholar 

  50. Smith MA, Morton CL, Phelps DA et al (2008) Stage 1 testing and pharmacodynamic evaluation of the HSP90 inhibitor alvespimycin (17-DMAG, KOS-1022) by the pediatric preclinical testing program. Pediatr Blood Cancer 51:34–41

    Article  PubMed  Google Scholar 

  51. Maris JM, Courtright J, Houghton PJ et al (2008) Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program. Pediatr Blood Cancer 50:581–587

    Article  PubMed  Google Scholar 

  52. Faisal A, Vaughan L, Bavetsias V et al (2011) The aurora kinase inhibitor CCT137690 downregulates MYCN and sensitizes MYCN-amplified neuroblastoma in vivo. Mol Cancer Ther 10:2115–2123

    Article  PubMed  CAS  Google Scholar 

  53. Kakodkar NC, Peddinti RR, Tian Y et al (2011) Sorafenib inhibits neuroblastoma cell proliferation and signaling, blocks angiogenesis, and impairs tumor growth. Pediatr Blood Cancer. doi:10.1002/pbc.240047

    Google Scholar 

  54. Yang F, Jove V, Buettner R et al (2012) Sorafenib inhibits endogenous and IL-6/S1P induced JAK2-STAT3 signaling in human neuroblastoma, associated with growth suppression and apoptosis. Cancer Biol Ther [Epub ahead of print]

  55. Grinshtein N, Datti A, Fujitani M et al (2011) Small molecule kinase inhibitor screen identifies polo-like kinase 1 as a target for neuroblastoma tumor-initiating cells. Cancer Res 71:1385–1395

    Article  PubMed  CAS  Google Scholar 

  56. Barr FA, Silljé HH, Nigg EA (2004) Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 5:429–441

    Article  PubMed  CAS  Google Scholar 

  57. Downward J (2009) Finding the weakness in cancer. N Engl J Med 361:922–924

    Article  PubMed  CAS  Google Scholar 

  58. Luo J, Emanuele MJ, Li D et al (2009) A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137:835–848

    Article  PubMed  CAS  Google Scholar 

  59. Chen Y, Takita J, Choi YL et al (2008) Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455:971–974

    Article  PubMed  CAS  Google Scholar 

  60. George RE, Sanda T, Hanna M et al (2008) Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 455:975–978

    Article  PubMed  CAS  Google Scholar 

  61. Bai RY, Dieter P, Peschel C et al (1998) Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity. Mol Cell Biol 18:6951–6961

    PubMed  CAS  Google Scholar 

  62. Bai RY, Ouyang T, Miething C et al (2000) Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood 96:4319–4327

    PubMed  CAS  Google Scholar 

  63. Slupianek A, Nieborowska-Skorska M, Hoser G et al (2001) Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res 61:2194–2199

    PubMed  CAS  Google Scholar 

  64. Amin HM, McDonnell TJ, Ma Y et al (2004) Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastic large cell lymphoma. Oncogene 23:5426–5434

    Article  PubMed  CAS  Google Scholar 

  65. Duyster J, Bai RY, Morris SW (2001) Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20:5623–5637

    Article  PubMed  CAS  Google Scholar 

  66. Shiota M, Fujimoto J, Semba T et al (1994) Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. Oncogene 9:1567–1574

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  68. Morris SW, Naeve C, Mathew P et al (1997) ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin’s lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene 14:2175–2188

    Article  PubMed  CAS  Google Scholar 

  69. Pulford K, Lamant L, Morris SW et al (1997) Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood 89:1394–1404

    PubMed  CAS  Google Scholar 

  70. Lamant L, Pulford K, Bischof D et al (2000) Expression of the ALK tyrosine kinase gene in neuroblastoma. Am J Pathol 156:1711–1721

    Article  PubMed  CAS  Google Scholar 

  71. Bresler SC, Wood C, Haglund EA et al (2011) Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci Transl Med 3:108ra114

    Google Scholar 

  72. Heuckmann JM, Hölzel M, Sos ML et al (2011) ALK mutations conferring differential resistance to structurally diverse ALK inhibitors. Clin Cancer Res 17:7394–7401

    Article  PubMed  CAS  Google Scholar 

  73. Carpenter EL, Haglund EA, Mace EM et al (2012) Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. Oncogene. doi:10.1038/onc.2011.647

    PubMed  Google Scholar 

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  1. Department of Pediatric Hematology/Oncology, Children’s Medical Center, Osaka City General Hospital, 2-13-22 Miyakojimahondouri, Miyakojimaku, Osaka, 534-0021, Japan

    Junichi Hara

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Correspondence to Junichi Hara.

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Hara, J. Development of treatment strategies for advanced neuroblastoma. Int J Clin Oncol 17, 196–203 (2012). https://doi.org/10.1007/s10147-012-0417-5

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