Advertisement

Molecular Targeted Therapy of Pediatric Neoplasms

  • Elizabeth A. Sokol
  • Navin R. Pinto
Chapter
Part of the Molecular Pathology Library book series (MPLB)

Abstract

Survival in pediatric cancer has overall increased significantly over the last several decades. However outcomes for patients with a subset of aggressive pediatric malignancies as well as those with relapsed and refractory cancer remain very poor. New targeted therapies are needed for these diseases. There are fewer mutations found in pediatric cancers than in most adult cancers, and more often, there is a single genetic driver caused by either a translocation or loss of heterozygosity.

Here we present an overview of a variety of targeted therapies in various stages of development in pediatrics. Targeting metabolic differences and aberrant signaling is frequently used in standard therapy. Increasingly, targeting cancer cell surface-associated proteins is being utilized as well. Cancer immunotherapy is a rapidly evolving field that utilizes the patient’s immune system in various ways to recognize and attack cancer cells. This includes antibody-dependent cell-mediated cytotoxicity, checkpoint inhibition, chimeric antigen receptor T cells, bispecific T-cell engagers, and other more experimental therapies. Additionally, we discuss several other modalities with unique mechanisms of targeting cancer cells.

There is a large amount of work being done to expand the use of targeted therapies in pediatrics. These studies require collaboration between investigators and institutions to broaden the availability of targeted therapies in the future.

Keywords

Pediatric oncology Precision medicine Immunotherapy 

References

  1. 1.
    Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220–41.CrossRefPubMedGoogle Scholar
  2. 2.
    Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer. 2009;115(7):1531–43.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ognjanovic S, Linabery AM, Charbonneau B, et al. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer. 2009;115(18):4218–26.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science. 2013;339(6127):1546–58.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ho DH, Whitecar JP, Luce JK, et al. l-asparagine requirement and the effect of l-asparaginase on the normal and leukemic human bone marrow. Cancer Res. 1970;30(2):466–72.PubMedGoogle Scholar
  6. 6.
    Howard SC, McCormick J, Pui CH, et al. Preventing and managing toxicities of high-dose methotrexate. Oncologist. 2016;21:1471–82.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bassiri H, Benavides A, Haber M, et al. Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma. Transl Pediatr. 2015;4(3):226–38.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Paul MK, Mukhopadhyay AK. Tyrosine kinase – role and significance in cancer. Int J Med Sci. 2004;1(2):101–15.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005;315(3):971–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Champagne MA, Fu CH, Chang M, et al. Higher dose imatinib for children with de novo chronic phase chronic myelogenous leukemia: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2011;57(1):56–62.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol. 2009;27(31):5175–81.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005–15.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Harvey RC, Mullighan CG, Wang X, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood. 2010;116(23):4874–84.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Din OS, Woll PJ. Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate. Ther Clin Risk Manag. 2008;4(1):149–62.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Tasian SK, Doral MY, Borowitz MJ, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood. 2012;120(4):833–42.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol. 2009;27(19):3126–32.CrossRefPubMedGoogle Scholar
  17. 17.
    van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879–86.CrossRefGoogle Scholar
  18. 18.
    Mueller S, Haas-Kogan DA. WEE1 kinase as a target for cancer therapy. J Clin Oncol. 2015;33(30):3485–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363(19):1801–11.CrossRefPubMedGoogle Scholar
  20. 20.
    Wagner F, Henningsen B, Lederer C, et al. Rapamycin blocks hepatoblastoma growth in vitro and in vivo implicating new treatment options in high-risk patients. Eur J Cancer. 2012;48(15):2442–50.CrossRefPubMedGoogle Scholar
  21. 21.
    Zibat A, Missiaglia E, Rosenberger A, et al. Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma. Oncogene. 2010;29(48):6323–30.CrossRefPubMedGoogle Scholar
  22. 22.
    Kaylani SZ, Xu J, Srivastava RK, et al. Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model. Biochem Biophys Res Commun. 2013;435(4):557–61.CrossRefPubMedGoogle Scholar
  23. 23.
    Mascarenhas L, Lyden ER, Rodeberg DA, et al. Randomized phase 2 trial of bevacizumab and temsirolimus in combination with vinorelbine (V) and cyclophosphamide (C) for first relapse/disease progression of rhabdomyosarcoma (RMS): a report from the Children’s Oncology Group. Presented at the American Society of Clinical Oncology, Chicago; 2014.Google Scholar
  24. 24.
    Houghton PJ, Morton CL, Kolb EA, et al. Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;50(4):799–805.CrossRefPubMedGoogle Scholar
  25. 25.
    Zolot RS, Basu S, Million RP. Antibody-drug conjugates. Nat Rev Drug Discov. 2013;12(4):259–60.CrossRefPubMedGoogle Scholar
  26. 26.
    Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363(19):1812–21.CrossRefPubMedGoogle Scholar
  27. 27.
    Roth M, Barris DM, Piperdi S, et al. Targeting glycoprotein NMB with antibody-drug conjugate, glembatumumab vedotin, for the treatment of osteosarcoma. Pediatr Blood Cancer. 2016;63(1):32–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Kolb EA, Gorlick R, Billups CA, et al. Initial testing (stage 1) of glembatumumab vedotin (CDX-011) by the pediatric preclinical testing program. Pediatr Blood Cancer. 2014;61(10):1816–21.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001;19(13):3244–54.CrossRefPubMedGoogle Scholar
  30. 30.
    Cooper TM, Franklin J, Gerbing RB, et al. AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: a report from the Children’s Oncology Group. Cancer. 2012;118(3):761–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Appelbaum FR, Bernstein ID. Gemtuzumab ozogamicin for acute myeloid leukemia. Blood. 2017;130:2373–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Scotlandi K, Benini S, Sarti M, et al. Insulin-like growth factor I receptor-mediated circuit in Ewing’s sarcoma/peripheral neuroectodermal tumor: a possible therapeutic target. Cancer Res. 1996;56(20):4570–4.PubMedGoogle Scholar
  33. 33.
    Benini S, Manara MC, Baldini N, et al. Inhibition of insulin-like growth factor I receptor increases the antitumor activity of doxorubicin and vincristine against Ewing’s sarcoma cells. Clin Cancer Res. 2001;7(6):1790–7.PubMedGoogle Scholar
  34. 34.
    Huber H, Eggert A, Janss AJ, et al. Angiogenic profile of childhood primitive neuroectodermal brain tumours/medulloblastomas. Eur J Cancer. 2001;37(16):2064–72.CrossRefPubMedGoogle Scholar
  35. 35.
    Akiyama T, Dass CR, Choong PF. Novel therapeutic strategy for osteosarcoma targeting osteoclast differentiation, bone-resorbing activity, and apoptosis pathway. Mol Cancer Ther. 2008;7(11):3461–9.CrossRefPubMedGoogle Scholar
  36. 36.
    McCarthy EF. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J. 2006;26:154–8.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Clynes RA, Towers TL, Presta LG, et al. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6(4):443–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Weiner GJ. Rituximab: mechanism of action. Semin Hematol. 2010;47(2):115–23.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Doronin II, Vishnyakova PA, Kholodenko IV, et al. Ganglioside GD2 in reception and transduction of cell death signal in tumor cells. BMC Cancer. 2014;14:295.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324–34.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Mody R, Naranjo A, Van Ryn C, 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. 2017;18(7):946–57.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Mody R, Naranjo A, Van Ryn C, et al. Phase II randomized trial of irinotecan/temozolomide (I/T) with temsirolimus (TEM) or dinutuximab plus granulocyte colony stimulating factor (DIN/GMCSF) in children with refractory or relapsed neuroblastoma: a report from the Children’s Oncology Group (COG). J Clin Oncol. 2016;34:10502.CrossRefGoogle Scholar
  43. 43.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Wolchok JD, Saenger Y. The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. Oncologist. 2008;13(Suppl 4):2–9.CrossRefGoogle Scholar
  46. 46.
    Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (Check Mate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182–91.CrossRefGoogle Scholar
  48. 48.
    Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017;35(19):2125–32.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Schellens JHM, Marabelle A, Zeigenfuss S, et al. Pembrolizumab for previously treated advanced cervical squamous cell cancer: preliminary results from the phase 2 KEYNOTE-158 study. J Clin Oncol. 2017;35(15_suppl):5514.CrossRefGoogle Scholar
  51. 51.
    Diaz LA, Marabelle A, Delord J-P, et al. Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-CRC. J Clin Oncol. 2017;35(15_suppl):3071.CrossRefGoogle Scholar
  52. 52.
    Maude SL, Teachey DT, Porter DL, et al. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125(26):4017–23.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Panel OKs CAR T therapy for leukemia. Cancer Discov. 2017;7(9):924.Google Scholar
  54. 54.
    Roberts ZJ, Better M, Bot A, et al. Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL. Leuk Lymphoma. 2017:1–12. https://doi.org/10.1080/10428194.2017.1387905.
  55. 55.
    Ahmed M, Cheung NK. Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy. FEBS Lett. 2014;588(2):288–97.CrossRefPubMedGoogle Scholar
  56. 56.
    Prapa M, Caldrer S, Spano C, et al. A novel anti-GD2/4-1BB chimeric antigen receptor triggers neuroblastoma cell killing. Oncotarget. 2015;6(28):24884–94.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Hong H, Stastny M, Brown C, et al. Diverse solid tumors expressing a restricted epitope of L1-CAM can be targeted by chimeric antigen receptor redirected T lymphocytes. J Immunother. 2014;37(2):93–104.CrossRefPubMedGoogle Scholar
  58. 58.
    Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009;69(12):4941–4.CrossRefPubMedGoogle Scholar
  59. 59.
    von Stackelberg A, Zugmaier G, Handgretinger R, et al. A phase 1/2 study of blinatumomab in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood. 2013;122:70.Google Scholar
  60. 60.
    Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood. 2012;119(26):6226–33.CrossRefPubMedGoogle Scholar
  61. 61.
    Topp MS, Stelljes M, Zugmaier G, et al. Blinatumomab retreatment after relapse in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia. Leukemia. 2018;32:562.CrossRefPubMedGoogle Scholar
  62. 62.
    Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14(9):642–62.CrossRefGoogle Scholar
  63. 63.
    Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Dis Model Mech. 2015;8(4):337–50.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Debets R, Donnadieu E, Chouaib S, et al. TCR-engineered T cells to treat tumors: seeing but not touching? Semin Immunol. 2016;28(1):10–21.CrossRefPubMedGoogle Scholar
  65. 65.
    Guo C, Manjili MH, Subjeck JR, et al. Therapeutic cancer vaccines: past, present, and future. Adv Cancer Res. 2013;119:421–75.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Virani S, Colacino JA, Kim JH, et al. Cancer epigenetics: a brief review. ILAR J. 2012;53(3–4):359–69.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Hummel TR, Wagner L, Ahern C, et al. A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a Children’s Oncology Group phase 1 consortium study. Pediatr Blood Cancer. 2013;60(9):1452–7.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Witt O, Milde T, Deubzer HE, et al. Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma or leukemia. Klin Padiatr. 2012;224(6):398–403.CrossRefPubMedGoogle Scholar
  69. 69.
    Fouladi M, Park JR, Stewart CF, et al. Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children’s Oncology Group phase I consortium report. J Clin Oncol. 2010;28(22):3623–9.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Almond JB, Cohen GM. The proteasome: a novel target for cancer chemotherapy. Leukemia. 2002;16(4):433–43.CrossRefPubMedGoogle Scholar
  71. 71.
    Houghton PJ, Morton CL, Kolb EA, et al. Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;50(1):37–45.CrossRefPubMedGoogle Scholar
  72. 72.
    Horton TM, Pati D, Plon SE, et al. A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children’s Oncology Group study. Clin Cancer Res. 2007;13(5):1516–22.CrossRefPubMedGoogle Scholar
  73. 73.
    Messinger YH, Gaynon PS, Sposto R, et al. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood. 2012;120(2):285–90.CrossRefPubMedGoogle Scholar
  74. 74.
    Garnett MJ, Edelman EJ, Heidorn SJ, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483(7391):570–5.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Stewart E, Goshorn R, Bradley C, et al. Targeting the DNA repair pathway in Ewing sarcoma. Cell Rep. 2014;9(3):829–41.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Matthay KK, Villablanca JG, Seeger RC, et al. 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. 1999;341(16):1165–73.CrossRefGoogle Scholar
  77. 77.
    Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–21.CrossRefPubMedGoogle Scholar
  78. 78.
    Zhou GB, Zhao WL, Wang ZY, et al. Retinoic acid and arsenic for treating acute promyelocytic leukemia. PLoS Med. 2005;2(1):e12.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PediatricsUniversity of Chicago Comer Children’s HospitalChicagoUSA
  2. 2.Department of PediatricsSeattle Children’s HospitalSeattleUSA

Personalised recommendations