Онкопедиатрия. 2016; 3: 8-15
Таргетные препараты в детской онкологии
https://doi.org/10.15690/onco.v3i1.1524Аннотация
Фундаментальные исследования в области молекулярной биологии, иммунологии, цитогенетики и эпигенетики опухолевой клетки позволили не только определить основные молекулярные пути злокачественной трансформации, но и модифицировать их с помощью таргетных препаратов (ТП). По мере расширения наших представлений о молекулярно-биологических основах онкогенеза расширяется спектр мишеней для таргетной терапии, блокирующей ангиогенез, сигнальные пути, потенциально онкогенные белки и ферменты. В настоящее время ТП стали неотъемлемой частью стандартов терапии взрослых больных со злокачественными опухолями. Роль и место ТП в лечении детей со злокачественными опухолями продолжают изучаться. Проводятся работы, определяющие побочные эффекты ТП у детей, анализируются результаты стандартных химиотерапевтических подходов и протоколов терапии с включением таргетных агентов. В настоящей статье обобщен современный мировой опыт применения ТП в детской онкологии, выделены показания и режимы введения ТП, определены перспективы дальнейших исследований в индивидуализации химиотерапевтического лечения детей со злокачественными новообразованиями на основании молекулярного «портрета» опухоли.
Список литературы
1. Ko JJ, Bernard B, Tran B, et al. Conditional Survival of Patients With Metastatic Testicular Germ Cell Tumors Treated With First-Line Curative Therapy. J Clin Oncol. 2016;34(7):714–20.
2. Валиев Т.Т., Барях Е.А., Зейналова П.А. и соавт. Оптимизация диагностики и лечения лимфомы Беркитта у детей, подростков и молодых взрослых. Клиническая онкогематология. Фундаментальные исследования и клиническая практика. 2014;7(2):175–183.
3. Иммунотерапия. Руководство для врачей под ред. академика РАН и РАМН Р.М. Хаитова, проф. Р.И. Атауллаханова. М.: ГОЭТАР-Медиа. 2012. 669 с.
4. Владимирская Е.Б. Механизмы кроветворения и лейкемогенеза. Цикл лекций. М.: Династия. 2007. 150 с.
5. Программное лечение заболеваний системы крови. Т. II. Под ред. В.Г. Савченко. М.: Практика. 2012. 1052 с.
6. Руководство по химиотерапии опухолевых заболеваний под ред. Н.И. Переводчиковой. М.: Практическая медицина. 2011. 510 с.
7. Лейкозы у детей. Под ред. Г.Л. Менкевича, С.А. Маяковой. М.: Практическая медицина. 2009. 381 с.
8. Ganta RR, Nasaka S, Gundeti S. Impact of Imatinib Adherence on the Cytogenetic Response in Pediatric Chronic Myeloid Leukemia — Chronic Phase. Indian J Pediatr. 2016 Feb 3. [Epub ahead of print].
9. Giona F, Putti MC, Micalizzi C, et al. Long-term results of high-dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience. Br J Haematol. 2015;170(3):398– 407.
10. Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012;13(9):936–45.
11. Guo Y, Liu T.F, Ruan M, et al. Efficacy and safety of imatinib for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in children. Zhongguo Dang Dai Er Ke Za Zhi. 2015;17(8):819–24.
12. Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood. 2009;114(27):5426–35.
13. Al-Jafar HA, Al-Mulla A, AlDallal S, et al. Successful nilotinib treatment in a child with chronic myeloid leukemia. Case Rep Oncol. 2015;8(1):122–7.
14. Müller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCRABL mutations. Blood. 2009;114(24):4944–53.
15. Suttorp M, Millot F. Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation. Hematology Am Soc Hematol Educ Program. 2010;2010:368–76.
16. Луговская С.А., Почтарь М.Е., Тупицын Н.Н. Иммунофенотипирование в диагностике гемобластозов. М.: Триада. 2005. 165 с.
17. Курильников А.Я. Мабтера — первые моноклональные антитела в терапии неходжкинских лимфом. Совр. онкол. 2002;4(1):25–28.
18. Reff M, Carner C, Chambers K, et al. Depletion of B-cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83:435–445.
19. Fanale MA, Younes A. Monoclonal antibodies in the treatment of non-Hodgkin’s lymphoma. Drugs. 2007;67(3):333–50.
20. Marcus R, Hagenbeek A. The therapeutic use of rituximab in non-Hodgkin’s lymphoma. Eur J Haematol. 2007;67:5–14.
21. Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Drugs. 2003;63(8):803–843.
22. Meinhardt A, Burkhardt B, Zimmermann M, et al. Phase II Window Study on Rituximab in Newly Diagnosed Pediatric Mature B-Cell Non-Hodgkin’s Lymphoma and Burkitt Leukemia. J Clin Oncol. 2010;28(19):3115–3121.
23. Bilic E, Femenic R, Conja J, et al. CD20-positive childhood B-non-Hodgkin lymphoma: morphology, immunophenotype and a novel treatment approach: a single center experience. Coll Antropol. 2010;34(1):171– 175.
24. Самочатова Е.В., Шелихова Л.Н., Белогурова М.Б. и др. Комбинированная химиоиммунотерапия больных неходжкинскими лимфомами из зрелых В-клеток возрастной группы до 18 лет: результаты многоцентрового исследования НХЛ 2004м с применением ритуксимаба и модифицированного протокола В-НХЛ ВФМ 90. Онкогематол. 2009;3:4–14.
25. Валиев Т.Т., Морозова О.В., Попа А.В. и соавт. Результаты лечения лимфомы Беркитта у детей. Гематология и трансфузиология. 2012;57(3, Прил.):34.
26. Hamedani FS, Cinar M, Mo Z, et al. Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL-2 family proteins in NPMALK(+) anaplastic large cell lymphoma. Leuk Res. 2014;38(4):503–8.
27. Gambacorti Passerini C, Farina F, Stasia A, et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. J Natl Cancer Inst. 2014;106(2):378.
28. Mossé YP, Lim MS, Voss SD, 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. 2013;14(6):472–80.
29. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–6.
30. Mikles B, Levine J, Gindin T, et al. Brentuximab vedotin (SGN-35) in a 3-year-old child with relapsed systemic anaplastic large cell lymphoma. J Pediatr Hematol Oncol. 2014;36(2):85–7.
31. Foyil KV, Bartlett NL. Brentuximab vedotin and crizotinib in anaplastic large-cell lymphoma. Cancer J. 2012;18(5):450–6.
32. Eyre TA, Khan D, Hall GW, et al. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: current and future perspectives in adult and paediatric disease. Eur J Haematol. 2014;93(6):455–68.
33. Kelly KM, Hodgson D, Appel B, et al. Children’s Oncology Group’s 2013 blueprint for research: Hodgkin lymphoma. Pediatr Blood Cancer. 2013;60(6):972–8.
34. Accardi F, Toscani D, Bolzoni M, et al. Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma- Induced Alterations of Bone Remodeling. Biomed Res Int. 2015. Р. 1–13.
35. Mitsiades CS, Mitsiades N, Poulaki V, et al. Activation of NF-kappaB and upregulation of intracellular antiapoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene. 2002;21(37):5673–83.
36. Hideshima T, Chauhan D, Richardson P, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem. 2002;277(19):16639–47.
37. Horton TM, Drachtman RA, Chen L, et al. A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children’s Oncology Group study. Br J Haematol. 2015;170(1):118–22.
38. Du XL, Chen Q. Recent advancements of bortezomib in acute lymphocytic leukemia treatment. Acta Haematol. 2013;129(4):207–14.
39. 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.
40. Messinger Y, Gaynon P, Raetz E, et al. Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia (TACL) consortium. Pediatr Blood Cancer. 2010;55(2):254–9.
41. Boye K, Del Prever AB, Eriksson M, et al. High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study. Pediatr Blood Cancer. 2014;61(5):840–5.
42. Ebb D, Holcombe G, Karen M, et al. Phase II Trial of Trastuzumab in Combination with Cytotoxic Chemotherapy for Treatment of Metastatic Osteosarcoma with Human Epidermal Growth Factor Receptor 2 Overexpression: A Report From the Children’s Oncology Group. Journal of Clinical Oncology. 2012;30(20): 2245–2551.
43. Whelan JS, Bielack SS, Marina N, et al. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment. Ann Oncol. 2015;26(2):407–14.
44. Grignani G, Palmerini E, Dileo P, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012;23(2):508–16.
45. Mei J, Zhu X, Wang Z, et al. VEGFR, RET, and RAF/MEK/ERK pathway take part in the inhibition of osteosarcoma MG63 cells with sorafenib treatment. Cell Biochem Biophys. 2014;69(1):151–6.
46. Pignochino Y, Dell’Aglio C, Basiricò M, et al The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 upregulation in osteosarcoma preclinical models. Clin Cancer Res. 2013;19(8):2117–31.
47. Grignani G, Palmerini E, Ferraresi V, et al. Sorafenib and everolimus for patients with unresectable highgrade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncol. 2015;16(1):98–107.
48. Grignani G, Palmerini E, Dileo P, et al. A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children’s Oncology Group Phase I Consortium Report. Clinical Cancer Research. 2012;18(21): 6011–6022.
49. Hiroto I, Rubnitz JE, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of the Multikinase Inhibitor Sorafenib in Combination With Clofarabine and Cytarabine in Pediatric Relapsed/ Refractory Leukemia. Journal of Clinical Oncology. 2011;29(24):3293–3300.
50. Schmid I, Häberle B, Albert MH, et al. Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. Pediatr Blood Cancer. 2012;58(4):539–44.
51. Fouladi M, Laningham F, Wu J, et al. Phase I study of everolimus in pediatric patients with refractory solid tumors. J Clin Oncol. 2007;25(30):4806–12.
52. Gajjar A, Stewart CF, Ellison DW, et al. Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a pediatric brain tumor consortium study. Clin Cancer Res. 2013;19(22):6305–12.
53. Gottardo NG, Hansford JR, McGlade JP, et al Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol. 2014;127(2):189–201.
54. Robinson GW, Orr BA, Wu G, et al. Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J Clin Oncol. 2015;33(24):2646–54.
55. Wetmore C, Boyett J, Li S, et al. Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children. Neuro Oncol. 2015;17(6):882–8.
56. DuBois SG, Marachelian A, Fox E, 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. 2016 Feb 16.
57. Qaddoumi I, Kocak M, Pai Panandiker AS, et al. Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas. Front Oncol. 2014;4:67.
58. Hummel TR, Salloum R, Drissi R, et al. A pilot study of bevacizumab-based therapy in patients with newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas. J Neurooncol. 2016;127(1):53–61.
59. Fouladi M, Stewart CF, Blaney SM, et al. A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: a pediatric brain tumor consortium study. Journal Neurooncology. 2013;114(2):173–9.
Oncopediatrics. 2016; 3: 8-15
Targeted Drugs in Pediatric Oncology
https://doi.org/10.15690/onco.v3i1.1524Abstract
Fundamental studies in molecular biology, immunology, cytogenetics and epigenetics of tumour cell revealed main molecular ways of neoplastic transformation and helped to perform their modification using targeted drugs (TD). With the development of knowledge in molecular and biologic basis of oncogenesis the spectrum of targets have been increased: suppression of angiogenesis, pathways, oncogene proteins, and enzymes. Nowadays TD became an essential part of malignancies therapy standards for adult patients. Place and role of TD in pediatric oncology are studying. Adverse events are revealing, treatment results of traditional chemotherapy protocols and programs with TD are analyzing. This review summarizes current international experience in targeted therapy, highlights indications and regimens of administration. Future perspectives in individualized chemotherapy based on tumor «molecular portrait» are demonstrated.
References
1. Ko JJ, Bernard B, Tran B, et al. Conditional Survival of Patients With Metastatic Testicular Germ Cell Tumors Treated With First-Line Curative Therapy. J Clin Oncol. 2016;34(7):714–20.
2. Valiev T.T., Baryakh E.A., Zeinalova P.A. i soavt. Optimizatsiya diagnostiki i lecheniya limfomy Berkitta u detei, podrostkov i molodykh vzroslykh. Klinicheskaya onkogematologiya. Fundamental'nye issledovaniya i klinicheskaya praktika. 2014;7(2):175–183.
3. Immunoterapiya. Rukovodstvo dlya vrachei pod red. akademika RAN i RAMN R.M. Khaitova, prof. R.I. Ataullakhanova. M.: GOETAR-Media. 2012. 669 s.
4. Vladimirskaya E.B. Mekhanizmy krovetvoreniya i leikemogeneza. Tsikl lektsii. M.: Dinastiya. 2007. 150 s.
5. Programmnoe lechenie zabolevanii sistemy krovi. T. II. Pod red. V.G. Savchenko. M.: Praktika. 2012. 1052 s.
6. Rukovodstvo po khimioterapii opukholevykh zabolevanii pod red. N.I. Perevodchikovoi. M.: Prakticheskaya meditsina. 2011. 510 s.
7. Leikozy u detei. Pod red. G.L. Menkevicha, S.A. Mayakovoi. M.: Prakticheskaya meditsina. 2009. 381 s.
8. Ganta RR, Nasaka S, Gundeti S. Impact of Imatinib Adherence on the Cytogenetic Response in Pediatric Chronic Myeloid Leukemia — Chronic Phase. Indian J Pediatr. 2016 Feb 3. [Epub ahead of print].
9. Giona F, Putti MC, Micalizzi C, et al. Long-term results of high-dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience. Br J Haematol. 2015;170(3):398– 407.
10. Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012;13(9):936–45.
11. Guo Y, Liu T.F, Ruan M, et al. Efficacy and safety of imatinib for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in children. Zhongguo Dang Dai Er Ke Za Zhi. 2015;17(8):819–24.
12. Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood. 2009;114(27):5426–35.
13. Al-Jafar HA, Al-Mulla A, AlDallal S, et al. Successful nilotinib treatment in a child with chronic myeloid leukemia. Case Rep Oncol. 2015;8(1):122–7.
14. Müller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCRABL mutations. Blood. 2009;114(24):4944–53.
15. Suttorp M, Millot F. Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation. Hematology Am Soc Hematol Educ Program. 2010;2010:368–76.
16. Lugovskaya S.A., Pochtar' M.E., Tupitsyn N.N. Immunofenotipirovanie v diagnostike gemoblastozov. M.: Triada. 2005. 165 s.
17. Kuril'nikov A.Ya. Mabtera — pervye monoklonal'nye antitela v terapii nekhodzhkinskikh limfom. Sovr. onkol. 2002;4(1):25–28.
18. Reff M, Carner C, Chambers K, et al. Depletion of B-cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83:435–445.
19. Fanale MA, Younes A. Monoclonal antibodies in the treatment of non-Hodgkin’s lymphoma. Drugs. 2007;67(3):333–50.
20. Marcus R, Hagenbeek A. The therapeutic use of rituximab in non-Hodgkin’s lymphoma. Eur J Haematol. 2007;67:5–14.
21. Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Drugs. 2003;63(8):803–843.
22. Meinhardt A, Burkhardt B, Zimmermann M, et al. Phase II Window Study on Rituximab in Newly Diagnosed Pediatric Mature B-Cell Non-Hodgkin’s Lymphoma and Burkitt Leukemia. J Clin Oncol. 2010;28(19):3115–3121.
23. Bilic E, Femenic R, Conja J, et al. CD20-positive childhood B-non-Hodgkin lymphoma: morphology, immunophenotype and a novel treatment approach: a single center experience. Coll Antropol. 2010;34(1):171– 175.
24. Samochatova E.V., Shelikhova L.N., Belogurova M.B. i dr. Kombinirovannaya khimioimmunoterapiya bol'nykh nekhodzhkinskimi limfomami iz zrelykh V-kletok vozrastnoi gruppy do 18 let: rezul'taty mnogotsentrovogo issledovaniya NKhL 2004m s primeneniem rituksimaba i modifitsirovannogo protokola V-NKhL VFM 90. Onkogematol. 2009;3:4–14.
25. Valiev T.T., Morozova O.V., Popa A.V. i soavt. Rezul'taty lecheniya limfomy Berkitta u detei. Gematologiya i transfuziologiya. 2012;57(3, Pril.):34.
26. Hamedani FS, Cinar M, Mo Z, et al. Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL-2 family proteins in NPMALK(+) anaplastic large cell lymphoma. Leuk Res. 2014;38(4):503–8.
27. Gambacorti Passerini C, Farina F, Stasia A, et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. J Natl Cancer Inst. 2014;106(2):378.
28. Mossé YP, Lim MS, Voss SD, 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. 2013;14(6):472–80.
29. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–6.
30. Mikles B, Levine J, Gindin T, et al. Brentuximab vedotin (SGN-35) in a 3-year-old child with relapsed systemic anaplastic large cell lymphoma. J Pediatr Hematol Oncol. 2014;36(2):85–7.
31. Foyil KV, Bartlett NL. Brentuximab vedotin and crizotinib in anaplastic large-cell lymphoma. Cancer J. 2012;18(5):450–6.
32. Eyre TA, Khan D, Hall GW, et al. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: current and future perspectives in adult and paediatric disease. Eur J Haematol. 2014;93(6):455–68.
33. Kelly KM, Hodgson D, Appel B, et al. Children’s Oncology Group’s 2013 blueprint for research: Hodgkin lymphoma. Pediatr Blood Cancer. 2013;60(6):972–8.
34. Accardi F, Toscani D, Bolzoni M, et al. Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma- Induced Alterations of Bone Remodeling. Biomed Res Int. 2015. R. 1–13.
35. Mitsiades CS, Mitsiades N, Poulaki V, et al. Activation of NF-kappaB and upregulation of intracellular antiapoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene. 2002;21(37):5673–83.
36. Hideshima T, Chauhan D, Richardson P, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem. 2002;277(19):16639–47.
37. Horton TM, Drachtman RA, Chen L, et al. A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children’s Oncology Group study. Br J Haematol. 2015;170(1):118–22.
38. Du XL, Chen Q. Recent advancements of bortezomib in acute lymphocytic leukemia treatment. Acta Haematol. 2013;129(4):207–14.
39. 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.
40. Messinger Y, Gaynon P, Raetz E, et al. Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia (TACL) consortium. Pediatr Blood Cancer. 2010;55(2):254–9.
41. Boye K, Del Prever AB, Eriksson M, et al. High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study. Pediatr Blood Cancer. 2014;61(5):840–5.
42. Ebb D, Holcombe G, Karen M, et al. Phase II Trial of Trastuzumab in Combination with Cytotoxic Chemotherapy for Treatment of Metastatic Osteosarcoma with Human Epidermal Growth Factor Receptor 2 Overexpression: A Report From the Children’s Oncology Group. Journal of Clinical Oncology. 2012;30(20): 2245–2551.
43. Whelan JS, Bielack SS, Marina N, et al. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment. Ann Oncol. 2015;26(2):407–14.
44. Grignani G, Palmerini E, Dileo P, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012;23(2):508–16.
45. Mei J, Zhu X, Wang Z, et al. VEGFR, RET, and RAF/MEK/ERK pathway take part in the inhibition of osteosarcoma MG63 cells with sorafenib treatment. Cell Biochem Biophys. 2014;69(1):151–6.
46. Pignochino Y, Dell’Aglio C, Basiricò M, et al The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 upregulation in osteosarcoma preclinical models. Clin Cancer Res. 2013;19(8):2117–31.
47. Grignani G, Palmerini E, Ferraresi V, et al. Sorafenib and everolimus for patients with unresectable highgrade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncol. 2015;16(1):98–107.
48. Grignani G, Palmerini E, Dileo P, et al. A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children’s Oncology Group Phase I Consortium Report. Clinical Cancer Research. 2012;18(21): 6011–6022.
49. Hiroto I, Rubnitz JE, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of the Multikinase Inhibitor Sorafenib in Combination With Clofarabine and Cytarabine in Pediatric Relapsed/ Refractory Leukemia. Journal of Clinical Oncology. 2011;29(24):3293–3300.
50. Schmid I, Häberle B, Albert MH, et al. Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. Pediatr Blood Cancer. 2012;58(4):539–44.
51. Fouladi M, Laningham F, Wu J, et al. Phase I study of everolimus in pediatric patients with refractory solid tumors. J Clin Oncol. 2007;25(30):4806–12.
52. Gajjar A, Stewart CF, Ellison DW, et al. Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a pediatric brain tumor consortium study. Clin Cancer Res. 2013;19(22):6305–12.
53. Gottardo NG, Hansford JR, McGlade JP, et al Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol. 2014;127(2):189–201.
54. Robinson GW, Orr BA, Wu G, et al. Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J Clin Oncol. 2015;33(24):2646–54.
55. Wetmore C, Boyett J, Li S, et al. Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children. Neuro Oncol. 2015;17(6):882–8.
56. DuBois SG, Marachelian A, Fox E, 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. 2016 Feb 16.
57. Qaddoumi I, Kocak M, Pai Panandiker AS, et al. Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas. Front Oncol. 2014;4:67.
58. Hummel TR, Salloum R, Drissi R, et al. A pilot study of bevacizumab-based therapy in patients with newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas. J Neurooncol. 2016;127(1):53–61.
59. Fouladi M, Stewart CF, Blaney SM, et al. A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: a pediatric brain tumor consortium study. Journal Neurooncology. 2013;114(2):173–9.
