Molecular Mechanisms of Hepatoblastoma

Abstract

Hepatoblastoma (HB) is the predominant primary liver tumor in children. While the prognosis is favorable when the tumor can be resected, the outcome is dismal for patients with progressed HB. Therefore, a better understanding of the molecular mechanisms responsible for HB is imperative for early detection and effective treatment. Sequencing analysis of human HB specimens unraveled the pivotal role of Wnt/β-catenin pathway activation in this disease. Nonetheless, β-catenin activation alone does not suffice to induce HB, implying the need for additional alterations. Perturbations of several pathways, including Hippo, Hedgehog, NRF2/KEAP1, HGF/c-Met, NK-1R/SP, and PI3K/AKT/mTOR cascades and aberrant activation of c-MYC, n-MYC, and EZH2 proto-oncogenes, have been identified in HB, although their role requires additional investigation. Here, we summarize the current knowledge on HB molecular pathogenesis, the relevance of the preclinical findings for the human disease, and the innovative therapeutic strategies that could be beneficial for the treatment of HB patients.

Keywords

hepatoblastoma - Wnt/β-catenin - Hippo - NRF2

Publication History

Article published online:
20 January 2021

• References

• 1 Darbari A, Sabin KM, Shapiro CN, Schwarz KB. Epidemiology of primary hepatic malignancies in U.S. children. Hepatology 2003; 38 (03) 560-566
• 2 Feng J, Polychronidis G, Heger U, Frongia G, Mehrabi A, Hoffmann K. Incidence trends and survival prediction of hepatoblastoma in children: a population-based study. Cancer Commun (Lond) 2019; 39 (01) 62
• 3 Celotti A, D'Amico G, Ceresoli M. et al. Hepatoblastoma of the adult: a systematic review of the literature. Surg Oncol 2016; 25 (03) 339-347
• 4 Mussa A, Ferrero GB. Screening hepatoblastoma in Beckwith-Wiedemann syndrome: a complex issue. J Pediatr Hematol Oncol 2015; 37 (08) 627
• 5 Trobaugh-Lotrario AD, López-Terrada D, Li P, Feusner JH. Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: clinical characteristics and rationale for surveillance screening. Pediatr Blood Cancer 2018; 65 (08) e27103
• 6 Clericuzio CL, Martin RA. Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia. Genet Med 2009; 11 (03) 220-222
• 7 Ito E, Sato Y, Kawauchi K. et al. Type 1a glycogen storage disease with hepatoblastoma in siblings. Cancer 1987; 59 (10) 1776-1780
• 8 Farmakis SG, Barnes AM, Carey JC, Braddock SR. Solid tumor screening recommendations in trisomy 18. Am J Med Genet A 2019; 179 (03) 455-466
• 9 Spector LG, Feusner JH, Ross JA. Hepatoblastoma and low birth weight. Pediatr Blood Cancer 2004; 43 (06) 706
• 10 Sharma D, Subbarao G, Saxena R. Hepatoblastoma. Semin Diagn Pathol 2017; 34 (02) 192-200
• 11 Qiao GL, Chen Z, Wang C. et al. Pure fetal histology subtype was associated with better prognosis of children with hepatoblastoma: a Chinese population-based study. J Gastroenterol Hepatol 2016; 31 (03) 621-627
• 12 López-Terrada D, Alaggio R, de Dávila MT. et al. Towards an international pediatric liver tumor consensus classification: Proceedings of the Los Angeles COG Liver Tumors Symposium. Mod pathology 2014; 27 (03) 472-491
• 13 Fazlollahi L, Hsiao SJ, Kochhar M, Mansukhani MM, Yamashiro DJ, Remotti HE. Malignant rhabdoid tumor, an aggressive tumor often misclassified as small cell variant of hepatoblastoma. Cancers (Basel) 2019; 11 (12) E1992
• 14 Zimmermann A. Hepatoblastoma with cholangioblastic features (‘cholangioblastic hepatoblastoma’) and other liver tumors with bimodal differentiation in young patients. Med Pediatr Oncol 2002; 39 (05) 487-491
• 15 Towbin AJ, Meyers RL, Woodley H. et al. 2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT). Pediatr Radiol 2018; 48 (04) 536-554
• 16 Maibach R, Roebuck D, Brugieres L. et al. Prognostic stratification for children with hepatoblastoma: the SIOPEL experience. Eur J Cancer 2012; 48 (10) 1543-1549
• 17 Trobaugh-Lotrario AD, Meyers RL, Feusner JH. Outcomes of patients with relapsed hepatoblastoma enrolled on Children's Oncology Group (COG) phase I and II studies. J Pediatr Hematol Oncol 2016; 38 (03) 187-190
• 18 Fuchs J, Rydzynski J, Von Schweinitz D. et al; Study Committee of the Cooperative Pediatric Liver Tumor Study Hb 94 for the German Society for Pediatric Oncology and Hematology. Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer 2002; 95 (01) 172-182
• 19 Hiyama E, Hishiki T, Watanabe K. et al. Resectability and tumor response after preoperative chemotherapy in hepatoblastoma treated by the Japanese Study Group for Pediatric Liver Tumor (JPLT)-2 protocol. J Pediatr Surg 2016; 51 (12) 2053-2057
• 20 Meyers RL, Maibach R, Hiyama E. et al. Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic Tumors International Collaboration. Lancet Oncol 2017; 18 (01) 122-131
• 21 Czauderna P. Hepatoblastoma throughout SIOPEL trials - clinical lessons learnt. Front Biosci (Elite Ed) 2012; 4: 470-479
• 22 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
• 23 Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nat Genet 2013; 45 (10) 1127-1133
• 24 Thorsson V, Gibbs DL, Brown SD. et al; Cancer Genome Atlas Research Network. The immune landscape of cancer. Immunity 2019; 51 (02) 411-412
• 25 Zanfardino M, Pane K, Mirabelli P, Salvatore M, Franzese M. TCGA-TCIA impact on radiogenomics cancer research: a systematic review. Int J Mol Sci 2019; 20 (23) E6033
• 26 Cairo S, Armengol C, De Reyniès 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 (06) 471-484
• 27 Cairo S, Wang Y, de Reyniès A. et al. Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. Proc Natl Acad Sci U S A 2010; 107 (47) 20471-20476
• 28 Hooks KB, Audoux J, Fazli H. et al. New insights into diagnosis and therapeutic options for proliferative hepatoblastoma. Hepatology 2018; 68 (01) 89-102
• 29 Carrillo-Reixach J, Torrens L, Simon-Coma M. et al. Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications. J Hepatol 2020; 73 (02) 328-341
• 30 Sumazin P, Chen Y, Treviño LR. et al. Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups. Hepatology 2017; 65 (01) 104-121
• 31 Nakagawa H, Fujita M, Fujimoto A. Genome sequencing analysis of liver cancer for precision medicine. Semin Cancer Biol 2019; 55: 120-127
• 32 Liotta L, Petricoin E. Molecular profiling of human cancer. Nat Rev Genet 2000; 1 (01) 48-56
• 33 Mavila N, Thundimadathil J. The emerging roles of cancer stem cells and Wnt/beta-catenin signaling in hepatoblastoma. Cancers (Basel) 2019; 11 (10) E1406
• 34 Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev 2011; 25 (10) 1010-1022
• 35 Crippa S, Ancey PB, Vazquez J. et al. Mutant CTNNB1 and histological heterogeneity define metabolic subtypes of hepatoblastoma. EMBO Mol Med 2017; 9 (11) 1589-1604
• 36 Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res 1999; 59 (02) 269-273
• 37 Jeng YM, Wu MZ, Mao TL, Chang MH, Hsu HC. Somatic mutations of beta-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma. Cancer Lett 2000; 152 (01) 45-51
• 38 Morcrette G, Hirsch TZ, Badour E. et al. APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. OncoImmunology 2019; 8 (06) e1583547
• 39 López-Terrada D, Gunaratne PH, Adesina AM. et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum Pathol 2009; 40 (06) 783-794
• 40 Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004; 303 (5663): 1483-1487
• 41 McCrea PD, Gottardi CJ. Beyond β-catenin: prospects for a larger catenin network in the nucleus. Nat Rev Mol Cell Biol 2016; 17 (01) 55-64
• 42 Zhang W, Meyfeldt J, Wang H. et al. β-Catenin mutations as determinants of hepatoblastoma phenotypes in mice. J Biol Chem 2019; 294 (46) 17524-17542
• 43 Bell D, Ranganathan S, Tao J, Monga SP. Novel advances in understanding of molecular pathogenesis of hepatoblastoma: a Wnt/β-catenin perspective. Gene Expr 2017; 17 (02) 141-154
• 44 Eichenmüller M, Trippel F, Kreuder M. et al. The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol 2014; 61 (06) 1312-1320
• 45 Gröbner SN, Worst BC, Weischenfeldt J. et al; ICGC PedBrain-Seq Project, ICGC MMML-Seq Project. The landscape of genomic alterations across childhood cancers. Nature 2018; 555 (7696): 321-327
• 46 Jia D, Dong R, Jing Y. et al. Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex. Hepatology 2014; 60 (05) 1686-1696
• 47 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
• 48 Paz-Yaacov N, Bazak L, Buchumenski I. et al. Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors. Cell Rep 2015; 13 (02) 267-276
• 49 Wang W, Smits R, Hao H, He C. Wnt/β-catenin signaling in liver cancers. Cancers (Basel) 2019; 11 (07) E926
• 50 Perugorria MJ, Olaizola P, Labiano I. et al. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol 2019; 16 (02) 121-136
• 51 MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009; 17 (01) 9-26
• 52 Shang S, Hua F, Hu ZW. The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget 2017; 8 (20) 33972-33989
• 53 Monga SP. β-Catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology 2015; 148 (07) 1294-1310
• 54 Yang A, Sisson R, Gupta A, Tiao G, Geller JI. Germline APC mutations in hepatoblastoma. Pediatr Blood Cancer 2018;65(04):
• 55 Forbes SA, Beare D, Boutselakis H. et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res 2017; 45 (D1): D777-D783
• 56 Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 2017; 169 (06) 985-999
• 57 Ding Y, Xi Y, Chen T. et al. Caprin-2 enhances canonical Wnt signaling through regulating LRP5/6 phosphorylation. J Cell Biol 2008; 182 (05) 865-872
• 58 Matsumoto S, Yamamichi T, Shinzawa K. et al. GREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling. Nat Commun 2019; 10 (01) 3882
• 59 Nejak-Bowen KN, Monga SP. Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad. Semin Cancer Biol 2011; 21 (01) 44-58
• 60 Maugeri-Saccà M, De Maria R. The Hippo pathway in normal development and cancer. Pharmacol Ther 2018; 186: 60-72
• 61 Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 2015; 15 (02) 73-79
• 62 Zhu C, Li L, Zhao B. The regulation and function of YAP transcription co-activator. Acta Biochim Biophys Sin (Shanghai) 2015; 47 (01) 16-28
• 63 Lin KC, Park HW, Guan KL. Regulation of the Hippo pathway transcription factor TEAD. Trends Biochem Sci 2017; 42 (11) 862-872
• 64 Huang J, Wu S, Barrera J, Matthews K, Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 2005; 122 (03) 421-434
• 65 Li H, Wolfe A, Septer S. et al. Deregulation of Hippo kinase signalling in human hepatic malignancies. Liver Int 2012; 32 (01) 38-47
• 66 Tao J, Calvisi DF, Ranganathan S. et al. Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology 2014; 147 (03) 690-701
• 67 Zhang S, Zhang J, Evert K. et al. The Hippo effector transcriptional coactivator with PDZ-binding motif cooperates with oncogenic β-catenin to induce hepatoblastoma development in mice and humans. Am J Pathol 2020; 190 (07) 1397-1413
• 68 Min Q, Molina L, Li J. et al. β-Catenin and Yes-associated protein 1 cooperate in hepatoblastoma pathogenesis. Am J Pathol 2019; 189 (05) 1091-1104
• 69 Smith JL, Rodríguez TC, Mou H. et al. YAP1 withdrawal in hepatoblastoma drives therapeutic differentiation of tumor cells to functional hepatocyte-like cells. Hepatology 2020;
• 70 Zhang J, Liu P, Tao J. et al. TEA domain transcription factor 4 is the major mediator of Yes-associated protein oncogenic activity in mouse and human hepatoblastoma. Am J Pathol 2019; 189 (05) 1077-1090
• 71 Dang CV. MYC on the path to cancer. Cell 2012; 149 (01) 22-35
• 72 Levens D. You don't muck with MYC. Genes Cancer 2010; 1 (06) 547-554
• 73 Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 1999; 19 (01) 1-11
• 74 Ranganathan S, Tan X, Monga SP. Beta-catenin and met deregulation in childhood hepatoblastomas. Pediatr Dev Pathol 2005; 8 (04) 435-447
• 75 Wang H, Lu J, Edmunds LR. et al. Coordinated activities of multiple Myc-dependent and Myc-independent biosynthetic pathways in hepatoblastoma. J Biol Chem 2016; 291 (51) 26241-26251
• 76 Eberherr C, Beck A, Vokuhl C. et al. Targeting excessive MYCN expression using MLN8237 and JQ1 impairs the growth of hepatoblastoma cells. Int J Oncol 2019; 54 (05) 1853-1863
• 77 Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15 (23) 3059-3087
• 78 Ruiz i Altaba A, Sánchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2002; 2 (05) 361-372
• 79 Eichenmüller M, Gruner I, Hagl B. et al. Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology 2009; 49 (02) 482-490
• 80 Oue T, Yoneda A, Uehara S, Yamanaka H, Fukuzawa M. Increased expression of the hedgehog signaling pathway in pediatric solid malignancies. J Pediatr Surg 2010; 45 (02) 387-392
• 81 Yamanaka H, Oue T, Uehara S, Fukuzawa M. Forskolin, a hedgehog signal inhibitor, inhibits cell proliferation and induces apoptosis in pediatric tumor cell lines. Mol Med Rep 2010; 3 (01) 133-139
• 82 Li YC, Deng YH, Guo ZH. et al. Prognostic value of hedgehog signal component expressions in hepatoblastoma patients. Eur J Med Res 2010; 15 (11) 468-474
• 83 Menegon S, Columbano A, Giordano S. The dual roles of NRF2 in cancer. Trends Mol Med 2016; 22 (07) 578-593
• 84 Comerford SA, Hinnant EA, Chen Y. et al. Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin. JCI Insight 2016; 1 (16) e88549
• 85 Peruzzi B, Bottaro DP. Targeting the c-Met signaling pathway in cancer. Clin Cancer Res 2006; 12 (12) 3657-3660
• 86 von Schweinitz D, Faundez A, Teichmann B. et al. Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma. Int J Cancer 2000; 85 (02) 151-159
• 87 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. Int J Oncol 2010; 36 (05) 1261-1267
• 88 Purcell R, Childs M, Maibach R. et al. HGF/c-Met related activation of β-catenin in hepatoblastoma. J Exp Clin Cancer Res 2011; 30: 96
• 89 Monga SP, Mars WM, Pediaditakis P. et al. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res 2002; 62 (07) 2064-2071
• 90 Vogt PK, Hart JR, Gymnopoulos M. et al. Phosphatidylinositol 3-kinase: the oncoprotein. Curr Top Microbiol Immunol 2010; 347: 79-104
• 91 Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature 2013; 497 (7448): 217-223
• 92 Hartmann W, Küchler 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
• 93 Liu P, Calvisi DF, Kiss A. et al. Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development. Oncotarget 2017; 8 (43) 73433-73447
• 94 Adebayo Michael AO, Ko S, Tao J. et al. Inhibiting glutamine-dependent mTORC1 activation ameliorates liver cancers driven by β-catenin mutations. Cell Metab 2019; 29 (05) 1135.e6-1150 e6
• 95 Muñoz M, Rosso M, Coveñas R. Neurokinin-1 receptor antagonists against hepatoblastoma. Cancers (Basel) 2019; 11 (09) E1258
• 96 Berger M, Neth O, Ilmer M. et al. Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo. J Hepatol 2014; 60 (05) 985-994
• 97 Garnier A, Ilmer M, Kappler R, Berger M. Therapeutic innovations for targeting hepatoblastoma. Anticancer Res 2016; 36 (11) 5577-5592
• 98 Gray SG, Eriksson T, Ekström C. et al. Altered expression of members of the IGF-axis in hepatoblastomas. Br J Cancer 2000; 82 (09) 1561-1567
• 99 Rainier S, Dobry CJ, Feinberg AP. Loss of imprinting in hepatoblastoma. Cancer Res 1995; 55 (09) 1836-1838
• 100 Honda S, Arai Y, Haruta M. et al. Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma. Br J Cancer 2008; 99 (11) 1891-1899
• 101 Regel I, Eichenmüller M, Joppien S. et al. IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors. Mol Cancer 2012; 11: 9
• 102 Akmal SN, Yun K, MacLay J, Higami Y, Ikeda T. Insulin-like growth factor 2 and insulin-like growth factor binding protein 2 expression in hepatoblastoma. Hum Pathol 1995; 26 (08) 846-851
• 103 Liu Z, Sun Q, Wang X. PLK1, a potential target for cancer therapy. Transl Oncol 2017; 10 (01) 22-32
• 104 Kats D, Ricker CA, Berlow NE. et al. Volasertib preclinical activity in high-risk hepatoblastoma. Oncotarget 2019; 10 (60) 6403-6417
• 105 Viré E, Brenner C, Deplus R. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006; 439 (7078): 871-874
• 106 Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med 2016; 22 (02) 128-134
• 107 Hajósi-Kalcakosz S, Dezső K, Bugyik E. et al. Enhancer of zeste homologue 2 (EZH2) is a reliable immunohistochemical marker to differentiate malignant and benign hepatic tumors. Diagn Pathol 2012; 7: 86
• 108 Schlachter K, Gyugos M, Halász J. et al. High tricellulin expression is associated with better survival in human hepatoblastoma. Histopathology 2014; 65 (05) 631-641
• 109 Wang Y, Xiao Y, Chen K. et al. Enhancer of zeste homolog 2 depletion arrests the proliferation of hepatoblastoma cells. Mol Med Rep 2016; 13 (03) 2724-2728
• 110 Lozano G, Zambetti GP. Gankyrin: an intriguing name for a novel regulator of p53 and RB. Cancer Cell 2005; 8 (01) 3-4
• 111 Higashitsuji H, Itoh K, Nagao T. et al. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med 2000; 6 (01) 96-99
• 112 Valanejad L, Lewis K, Wright M. et al. FXR-Gankyrin axis is involved in development of pediatric liver cancer. Carcinogenesis 2017; 38 (07) 738-747
• 113 Cast A, Valanejad L, Wright M. et al. C/EBPα-dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer. Hepatology 2018; 67 (05) 1857-1871
• 114 Toiyama Y, Inoue Y, Yasuda H. et al. DPEP1, expressed in the early stages of colon carcinogenesis, affects cancer cell invasiveness. J Gastroenterol 2011; 46 (02) 153-163
• 115 Cui X, Liu X, Han Q. et al. DPEP1 is a direct target of miR-193a-5p and promotes hepatoblastoma progression by PI3K/Akt/mTOR pathway. Cell Death Dis 2019; 10 (10) 701
• 116 Gil-García B, Baladrón V. The complex role of NOTCH receptors and their ligands in the development of hepatoblastoma, cholangiocarcinoma and hepatocellular carcinoma. Biol Cell 2016; 108 (02) 29-40
• 117 Nagai H, Naka T, Terada Y. et al. Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas. J Hum Genet 2003; 48 (02) 65-69
• 118 Honda S, Miyagi H, Suzuki H. et al. RASSF1A methylation indicates a poor prognosis in hepatoblastoma patients. Pediatr Surg Int 2013; 29 (11) 1147-1152
• 119 Gray SG, Hartmann W, Eriksson T. et al. Expression of genes involved with cell cycle control, cell growth and chromatin modification are altered in hepatoblastomas. Int J Mol Med 2000; 6 (02) 161-169
• 120 Trobaugh-Lotrario AD, Venkatramani R, Feusner JH. Hepatoblastoma in children with Beckwith-Wiedemann syndrome: does it warrant different treatment?. J Pediatr Hematol Oncol 2014; 36 (05) 369-373
• 121 Delmore JE, Issa GC, Lemieux ME. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011; 146 (06) 904-917
• 122 Ma L, Wang X, Jia T, Wei W, Chua MS, So S. Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells. Oncotarget 2015; 6 (28) 25390-25401
• 123 Jia J, Qiao Y, Pilo MG. et al. Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade. PLoS One 2017; 12 (09) e0184068
• 124 Kieran MW, Chisholm J, Casanova M. et al. Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Neuro-oncol 2017; 19 (11) 1542-1552
• 125 Grüllich C. Cabozantinib: multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2. Recent Results Cancer Res 2018; 211: 67-75
• 126 Osanto S, van der Hulle T. Cabozantinib in the treatment of advanced renal cell carcinoma in adults following prior vascular endothelial growth factor targeted therapy: clinical trial evidence and experience. Ther Adv Urol 2018; 10 (03) 109-123
• 127 Dhillon S. Ivosidenib: first global approval. Drugs 2018; 78 (14) 1509-1516
• 128 Richon VM, Garcia-Vargas J, Hardwick JS. Development of vorinostat: current applications and future perspectives for cancer therapy. Cancer Lett 2009; 280 (02) 201-210
• 129 Deroanne CF, Bonjean K, Servotte S. et al. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 2002; 21 (03) 427-436
• 130 Kim GD, Choi YH, Dimtchev A, Jeong SJ, Dritschilo A, Jung M. Sensing of ionizing radiation-induced DNA damage by ATM through interaction with histone deacetylase. J Biol Chem 1999; 274 (44) 31127-31130
• 131 Li AY, McCusker MG, Russo A. et al. RET fusions in solid tumors. Cancer Treat Rev 2019; 81: 101911
• 132 Yang Y, Zhou J, Zhou J. et al. Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial. Lancet Respir Med 2020; 8 (01) 45-53
• 133 Mesa RA. Tipifarnib: farnesyl transferase inhibition at a crossroads. Expert Rev Anticancer Ther 2006; 6 (03) 313-319
• 134 Liu M, Liu H, Chen J. Mechanisms of the CDK4/6 inhibitor palbociclib (PD 0332991) and its future application in cancer treatment (Review). Oncol Rep 2018; 39 (03) 901-911
• 135 Roskoski Jr R. Targeting ERK1/2 protein-serine/threonine kinases in human cancers. Pharmacol Res 2019; 142: 151-168
• 136 Scott LJ. Larotrectinib: first global approval. Drugs 2019; 79 (02) 201-206
• 137 Chen Y, Du H. The promising PARP inhibitors in ovarian cancer therapy: from Olaparib to others. Biomed Pharmacother 2018; 99: 552-560
• 138 Niu NK, Wang ZL, Pan ST. et al. Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway. Drug Des Devel Ther 2015; 9: 1555-1584
• 139 Garbe C, Eigentler TK. Vemurafenib. Recent Results Cancer Res 2018; 211: 77-89
• 140 Duvoux C, Toso C. mTOR inhibitor therapy: does it prevent HCC recurrence after liver transplantation?. Transplant Rev (Orlando) 2015; 29 (03) 168-174
• 141 Zheng L, Li H, Mo Y, Qi G, Liu B, Zhao J. Autophagy inhibition sensitizes LY3023414-induced anti-glioma cell activity in vitro and in vivo . Oncotarget 2017; 8 (58) 98964-98973
• 142 Makita S, Tobinai K. Targeting EZH2 with tazemetostat. Lancet Oncol 2018; 19 (05) 586-587
• 143 Markham A. Erdafitinib: first global approval. Drugs 2019; 79 (09) 1017-1021
• 144 Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies?. Expert Opin Emerg Drugs 2019; 24 (03) 153-171
• 145 Al-Rasheed NM, Al-Oteibi MM, Al-Manee RZ. et al. Simvastatin prevents isoproterenol-induced cardiac hypertrophy through modulation of the JAK/STAT pathway. Drug Des Devel Ther 2015; 9: 3217-3229
• 146 McKian KP, Haluska P. Cixutumumab. Expert Opin Investig Drugs 2009; 18 (07) 1025-1033
• 147 Ettrich TJ, Seufferlein T. Regorafenib. Recent Results Cancer Res 2018; 211: 45-56
• 148 Strumberg D, Schultheis B. Regorafenib for cancer. Expert Opin Investig Drugs 2012; 21 (06) 879-889
• 149 Metro G, Chiari R, Baldi A, De Angelis V, Minotti V, Crinò L. Selumetinib: a promising pharmacologic approach for KRAS-mutant advanced non-small-cell lung cancer. Future Oncol 2013; 9 (02) 167-177