Novel therapeutics in hepatoblastoma
Main Article Content
Abstract
Hepatoblastoma is the most common primary liver malignancy in children less than 5 years of age. The incidence of this cancer is increasing but therapy for hepatoblastoma has not significantly changed and it is primarily managed with combinations of surgery and chemotherapy. Conventional chemotherapy regimens include cisplatin, as it is currently the most effective agent for this tumor. Unfortunately, with the current modalities, the prognosis for advanced-stage disease remains poor due to the high rate of recurrence and/or the development of chemoresistance. As the understanding of the pathophysiology of hepatoblastoma deepens, there is a burgeoning interest in developing novel therapeutic agents for hepatoblastoma, including targeted therapies. In the current review, we discuss the use of major signaling pathways and their effector molecules such as β-catenin, c-MET, mTOR, PIM kinases, and PLK1 as therapeutic targets. In addition, we explore various alternative pre-clinical approaches that have been described in hepatoblastoma, including immunotherapy, differentiation agents, micro-RNAs, and targeted drug delivery. Finally, we outline the therapies currently under investigation in pre-clinical and clinical settings that show promising preliminary results for hepatoblastoma treatment.
Keywords:
hepatoblastoma, chemotherapy, targeted therapy
Article Details
How to Cite
WADHWANI, Nikita; MARAYATI, Raoud; BEIERLE, Elizabeth A..
Novel therapeutics in hepatoblastoma.
Medical Research Archives, [S.l.], v. 8, n. 6, june 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2163>. Date accessed: 24 apr. 2024.
doi: https://doi.org/10.18103/mra.v8i6.2163.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. Hadzic N, Finegold MJ. Liver Neoplasia in Children. Clinics in Liver Disease. 2011;15(2):443-462.
3. Spector LG, Birch J. The epidemiology of hepatoblastoma. Pediatr Blood Cancer. 2012;59(5):776-779.
4. Aronson DC, Schnater JM, Staalman CR, et al. Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol. 2005;23(6):1245-1252.
5. Aronson DC, Czauderna P, Maibach R, Perilongo G, Morland B. The treatment of hepatoblastoma: Its evolution and the current status as per the SIOPEL trials. J Indian Assoc Pediatr Surg. 2014;19(4):201-207.
6. Roebuck DJ, Sebire NJ, Pariente D. Assessment of extrahepatic abdominal extension in primary malignant liver tumours of childhood. Pediatric Radiology. 2007;37(11):1096-1100.
7. Malogolowkin MH, Katzenstein HM, Meyers RL, et al. Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children's Oncology Group. J Clin Oncol. 2011;29(24):3301-3306.
8. Evans AE, Land VJ, Newton WA, Randolph JG, Sather HN, Tefft M. Combination chemotherapy (vincristine, adriamycin, cyclophosphamide, and 5-fluorouracil) in the treatment of children with malignant hepatoma. Cancer. 1982;50(5):821-826.
9. Filler RM, Ehrlich PF, Greenberg ML, Babyn PS. Preoperative chemotherapy in hepatoblastoma. Surgery. 1991;110(4):591-596; discussion 596-597.
10. Pierro A, Langevin AM, Filler RM, Liu P, Phillips MJ, Greenberg ML. Preoperative chemotherapy in ‘Unresectable’ hepatoblastoma. Journal of Pediatric Surgery. 1989;24(1):24-29.
11. Ortega JA, Krailo MD, Haas JE, et al. Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol. 1991;9(12):2167-2176.
12. Kremer N, Walther AE, Tiao GM. Management of hepatoblastoma: an update. Curr Opin Pediatr. 2014;26(3):362-369.
13. Hiyama E. Pediatric hepatoblastoma: diagnosis and treatment. Transl Pediatr. 2014;3(4):293-299.
14. Perilongo G, Maibach R, Shafford E, et al. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med. 2009;361(17):1662-1670.
15. Zsiros J, Maibach R, Shafford E, et al. Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol. 2010;28(15):2584-2590.
16. Katzenstein HM, Langham MR, Malogolowkin MH, et al. Minimal adjuvant chemotherapy for children with hepatoblastoma resected at diagnosis (AHEP0731): a Children's Oncology Group, multicentre, phase 3 trial. Lancet Oncol. 2019;20(5):719-727.
17. von Schweinitz D, Byrd DJ, Hecker H, et al. Efficiency and toxicity of ifosfamide, cisplatin and doxorubicin in the treatment of childhood hepatoblastoma. Study Committee of the Cooperative Paediatric Liver Tumour Study HB89 of the German Society for Paediatric Oncology and Haematology. Eur J Cancer. 1997;33(8):1243-1249.
18. Weinblatt ME, Siegel SE, Siegel MM, Stanley P, Weitzman JJ. Preoperative chemotherapy for unresectable primary hepatic malignancies in children. Cancer. 1982;50(6):1061-1064.
19. Alisi A, Cho CW, Locatelli F, Fruci D. Multidrug Resistance and Cancer Stem Cells in Neuroblastoma and Hepatoblastoma. International Journal of Molecular Sciences. 2013;14(12).
20. Lee H, El Jabbour T, Ainechi S, et al. General paucity of genomic alteration and low tumor mutation burden in refractory and metastatic hepatoblastoma: comprehensive genomic profiling study. Hum Pathol. 2017;70:84-91.
21. Aguiar TFM, Carneiro TN, da Costa CML, Rosenberg C, da Cunha IW, Krepischi ACV. The genetic and epigenetic landscapes of hepatoblastomas. Applied Cancer Research. 2017;37(1):20.
22. Russell JO, Monga SP. Wnt/β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology. Annual Review of Pathology: Mechanisms of Disease. 2018;13(1):351-378.
23. Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T. Childhood Hepatoblastomas Frequently Carry a Mutated Degradation Targeting Box of the β-Catenin Gene. Cancer Research. 1999;59(2):269.
24. Cairo S, Armengol C, De Reynies A, et al. Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell. 2008;14(6):471-484.
25. Sumazin P, Chen Y, Treviño LR, et al. Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups. Hepatology. 2017;65(1):104-121.
26. Sang Park W, Ra Oh R, Young Park J, et al. Nuclear localization of β-catenin is an important prognostic factor in hepatoblastoma. The Journal of Pathology. 2001;193(4):483-490.
27. Tang Y, Berlind J, Mavila N. Inhibition of CREB binding protein-beta-catenin signaling down regulates CD133 expression and activates PP2A-PTEN signaling in tumor initiating liver cancer cells. Cell Communication and Signaling. 2018;16(1):9.
28. Ellerkamp V, Lieber J, Nagel C, et al. Pharmacological inhibition of beta-catenin in hepatoblastoma cells. Pediatric Surgery International. 2013;29(2):141-149.
29. Han ZG. Mutational landscape of hepatoblastoma goes beyond the Wnt-beta-catenin pathway. Hepatology. 2014;60(5):1476-1478.
30. Koch A, Weber N, Waha A, et al. Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas. The Journal of Pathology. 2004;204(5):546-554.
31. Huang S, Chen J, Tian R, et al. Down-regulation of dishevelled-2 inhibits cell proliferation and invasion in hepatoblastoma. Pediatric Blood & Cancer. 2018;65(7):e27032.
32. Purcell R, Childs M, Maibach R, et al. HGF/c-Met related activation of β-catenin in hepatoblastoma. Journal of Experimental & Clinical Cancer Research. 2011;30(1):96.
33. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat. 2008;11(1-2):32-50.
34. West KA, Castillo SS, Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 2002;5(6):234-248.
35. Hartmann W, Kuchler J, Koch A, et al. Activation of phosphatidylinositol-3'-kinase/AKT signaling is essential in hepatoblastoma survival. Clin Cancer Res. 2009;15(14):4538-4545.
36. Adebayo Michael AO, Ko S, Tao J, et al. Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations. Cell Metabolism. 2019;29(5):1135-1150.e1136.
37. Liu P, Calvisi DF, Kiss A, et al. Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development. Oncotarget; Vol 8, No 43. 2017.
38. 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. European Journal of Cancer. 2012;48(15):2442-2450.
39. Molina L, Yang H, Adebayo Michael AO, et al. mTOR inhibition affects Yap1-β-catenin-induced hepatoblastoma growth and development. Oncotarget; Vol 10, No 15. 2019.
40. Grotegut S, Kappler R, Tarimoradi S, Lehembre F, Christofori G, Von Schweinitz D. Hepatocyte growth factor protects hepatoblastoma cells from chemotherapy-induced apoptosis by AKT activation. International journal of oncology. 2010;36(5):1261-1267.
41. Ventura J-J, Nebreda ÁR. Protein kinases and phosphatases as therapeutic targets in cancer. Clinical and Translational Oncology. 2006;8(3):153-160.
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