Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Review Article

Potential Therapeutic Strategies to Combat HCC

Author(s): Sidra Altaf*, Faiza Saleem, Azam Ali Sher and Ashiq Ali

Volume 15, Issue 7, 2022

Published on: 27 April, 2022

Article ID: e030122199802 Pages: 14

DOI: 10.2174/1874467215666220103111009

Price: $65

Abstract

Hepatocellular carcinoma (HCC) is a complex, life-threatening and most common neoplasm in the world. HCC tumors are genetically and phenotypically heterogeneous, and involve various molecular mechanisms and stimulation of several signaling pathways, such as Vascular Endothelial Growth Factor, Epidermal Growth Factor Receptors (EGFR), Insulin growth factor, Ras/extracellular signal-stimulated kinase, the mammalian goal of rapamycin (mTOR), c-mesenchymal- epithelial transition factor-1 (c-Met), Hedgehog, Wnt and apoptotic signaling. Lately, in patients, multi-kinase cascade blockers, such as sorafenib, selumetinib and regorafenib, have increased the survival rate of progressive HCC. This development presents a step forward towards the therapy of liver cancer infection and attests that molecular systemic rehabilitation can be useful in HCC treatment. The development of these systemic therapeutic agents has further expanded the research area for surplus molecular mediators to auxiliary increase the cure rate of patients. This article reviews the complete focus on cascades, current enduring clinical tests by means of HCC therapeutic mediators, and imminent prospects in the cure of HCC.

Keywords: Liver cancer, signaling pathway, therapeutic agents, hepatocellular carcinoma (HCC), vascular endothelial growth factors, angiogenesis.

Graphical Abstract
[1]
Zhou, J.; Vallejo, J.; Kluetz, P.; Pazdur, R.; Kim, T.; Keegan, P.; Farrell, A.; Beaver, J.A.; Sridhara, R. Overview of oncology and hematology drug approvals at us food and drug administration between 2008 and 2016. J. Natl. Cancer Inst., 2019, 111(5), 449-458.
[http://dx.doi.org/10.1093/jnci/djy130] [PMID: 30085269]
[2]
Gnanasakthy, A.; DeMuro, C.; Clark, M.; Haydysch, E.; Ma, E.; Bonthapally, V. Patient-reported outcomes labeling for products approved by the office of hematology and oncology products of the US food and drug administration (2010-2014). J. Clin. Oncol., 2016, 34(16), 1928-1934.
[http://dx.doi.org/10.1200/JCO.2015.63.6480] [PMID: 27069082]
[3]
Wang, Q.; Peng, H.; Qi, X.; Wu, M.; Zhao, X. Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence. Signal Transduct. Target. Ther., 2020, 5(1), 137.
[http://dx.doi.org/10.1038/s41392-020-0199-6] [PMID: 32728057]
[4]
Nault, J.C.; Cheng, A.L.; Sangro, B.; Llovet, J.M. Milestones in the pathogenesis and management of primary liver cancer. J. Hepatol., 2020, 72(2), 209-214.
[http://dx.doi.org/10.1016/j.jhep.2019.11.006] [PMID: 31954486]
[5]
Seehawer, M.; Heinzmann, F.; D’Artista, L.; Harbig, J.; Roux, P.F.; Hoenicke, L.; Dang, H.; Klotz, S.; Robinson, L.; Doré, G.; Rozenblum, N.; Kang, T.W.; Chawla, R.; Buch, T.; Vucur, M.; Roth, M.; Zuber, J.; Luedde, T.; Sipos, B.; Longerich, T.; Heikenwälder, M.; Wang, X.W.; Bischof, O.; Zender, L. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature, 2018, 562(7725), 69-75.
[http://dx.doi.org/10.1038/s41586-018-0519-y] [PMID: 30209397]
[6]
Ringelhan, M.; Pfister, D.; O’Connor, T.; Pikarsky, E.; Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol., 2018, 19(3), 222-232.
[http://dx.doi.org/10.1038/s41590-018-0044-z] [PMID: 29379119]
[7]
Torrecilla, S.; Sia, D.; Harrington, A.N.; Zhang, Z.; Cabellos, L.; Cornella, H.; Moeini, A.; Camprecios, G.; Leow, W.Q.; Fiel, M.I.; Hao, K.; Bassaganyas, L.; Mahajan, M.; Thung, S.N.; Villanueva, A.; Florman, S.; Schwartz, M.E.; Llovet, J.M. Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. J. Hepatol., 2017, 67(6), 1222-1231.
[http://dx.doi.org/10.1016/j.jhep.2017.08.013] [PMID: 28843658]
[8]
Atallah, J.; Khachfe, H.H.; Berro, J.; Assi, H.I. The use of heparin and heparin-like molecules in cancer treatment: a review. Cancer Treat. Res. Commun., 2020, 24, 100192.
[http://dx.doi.org/10.1016/j.ctarc.2020.100192] [PMID: 32673846]
[9]
Arvind, K.P.; Eric, K.S.; Juan, P.A.; Talat, A.I.; Edward, R.G.; Jonathan, B.; Joshua, A.B.; David, G.H.; Javid, M. Mechanisms of VEGF (Vascular Endothelial Growth Factor) inhibitor-associated hypertension and vascular disease. Hypertension, 2018, 71(2), e1-e8.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10271]
[10]
Baeyens, N. Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point. Elife 4:eo4645.
[http://dx.doi.org/10.7554/eLife.04645]
[11]
Xie, Y.; Su, N.; Yang, J.; Tan, Q.; Huang, S.; Jin, M.; Ni, Z.; Zhang, B.; Zhang, D.; Luo, F.; Chen, H.; Sun, X.; Feng, J.Q.; Qi, H.; Chen, L. FGF/FGFR signaling in health and disease. Signal Transduct. Target. Ther., 2020, 5(1), 181.
[http://dx.doi.org/10.1038/s41392-020-00222-7] [PMID: 32879300]
[12]
Szybowska, P.; Kostas, M.; Wesche, J.; Wiedlocha, A.; Haugsten, E.M. Cancer mutations in FGFR2 prevent a negative feedback loop mediated by the ERK1/2 pathway. Cells, 2019, 8(6), 518.
[http://dx.doi.org/10.3390/cells8060518]
[13]
Young, K.C., Fangxin, H., Christos, V., Heather, H.C., Peter H., Edith, PM., James, A.Z., Percy, I.S., Robert, J.G., Shuli, L., Lisa, M.M., Larry, V.R., David, P., Mickey, P.W., Stanley, R.H., Aaron, M., Barbara, A.C., Carlos, L.A., Lyndsay, N.H., Peter, J.O’Dwyer, Alice, P.C., Keith, T. F. Phase II study of AZD4547 in patients with tumors harboring aberrations in the FGFR pathway: results from the NCI-MATCH Trial (EAY131) subprotocol W. J. Clin. Oncol., 2020, 38(21), 2407-2417.
[http://dx.doi.org/10.1200/JCO.19.02630] [PMID: 32463741]
[14]
Jain, S.; Deore, S.V.; Ghadi, R.; Chaudhari, D.; Kuche, K.; Katiyar, S.S. Tumor microenvironment responsive VEGF-antibody functionalized pH sensitive liposomes of Docetaxel for augmented breast cancer therapy. Mater. Sci. Eng. C, 2020, 121, 111832.
[http://dx.doi.org/10.1016/j.msec.2020.111832]
[15]
Lacal, P.M.; Graziani, G. Therapeutic implication of vascular endothelial growth factor receptor-1 (VEGFR-1) targeting in cancer cells and tumor microenvironment by competitive and non-competitive inhibitors. Pharmacol. Res., 2018, 136(August), 97-107.
[http://dx.doi.org/10.1016/j.phrs.2018.08.023] [PMID: 30170190]
[16]
Terry, K.; Copur, M.S. Molecular targeted therapy of hepatocellular carcinoma. J. Cancer Ther., 2013, 4, 426-439.
[17]
Nair, A.; Kelie, R.; Martha, B.D.; Weishi, V.Y.; Lisa, R.; Patricia, K.; Richard, P. FDA Supplemental approval summary: lenvatinib for the treatment of unresectable hepatocellular carcinoma. Oncologist, 2021, 26(3), e484-e491.
[http://dx.doi.org/10.1002/onco.13566] [PMID: 33044793]
[18]
Huang, A.; Yang, X.R.; Chung, W.Y.; Dennison, A.R.; Zhou, J. Targeted therapy for hepatocellular carcinoma. Signal Transduct. Target. Ther., 2020, 5(1), 146.
[http://dx.doi.org/10.1038/s41392-020-00264-x] [PMID: 32782275]
[19]
Kudo, M. Lenvatinib may drastically change the treatment landscape of hepatocellular carcinoma. Liver Cancer, 2018, 7(1), 1-19.
[http://dx.doi.org/10.1159/000487148] [PMID: 29662829]
[20]
Personeni, N.; Pressiani, T.; Rimassa, L. Lenvatinib for the treatment of unresectable hepatocellular carcinoma: evidence to date. J. Hepatocell. Carcinoma, 2019, 6, 31-39.
[http://dx.doi.org/10.2147/JHC.S168953] [PMID: 30775342]
[21]
Ferrara, N.; Adamis, A.P. Ten years of anti-vascular endothelial growth factor therapy. Nat. Rev. Drug Discov., 2016, 15(6), 385-403.
[http://dx.doi.org/10.1038/nrd.2015.17] [PMID: 26775688]
[22]
Garcia, J. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat. Rev., 2020, 86, 102017.
[http://dx.doi.org/10.1016/j.ctrv.2020.102017]
[23]
Stinchcombe, T.E.; Jänne, P.A.; Wang, X.; Bertino, E.M.; Weiss, J.; Bazhenova, L.; Gu, L.; Lau, C.; Paweletz, C.; Jaslowski, A.; Gerstner, G.J.; Baggstrom, M.Q.; Graziano, S.; Bearden, J., III; Vokes, E.E. Effect of erlotinib plus bevacizumab vs. erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol., 2019, 5(10), 1448-1455.
[http://dx.doi.org/10.1001/jamaoncol.2019.1847] [PMID: 31393548]
[24]
Medavaram, S.; Zhang, Y. Emerging therapies in advanced hepatocellular carcinoma. Exp. Hematol. Oncol., 2018, 7(1), 17.
[http://dx.doi.org/10.1186/s40164-018-0109-6] [PMID: 30087805]
[25]
Kim, D.W.; Talati, C.; Kim, R. Hepatocellular carcinoma (HCC): beyond sorafenib-chemotherapy. J. Gastrointest. Oncol., 2017, 8(2), 256-265.
[http://dx.doi.org/10.21037/jgo.2016.09.07] [PMID: 28480065]
[26]
Mossenta, M.; Busato, D.; Baboci, L.; Cintio, F.D.; Toffoli, G.; Bo, M.D. New insight into therapies targeting angiogenesis in hepatocellular carcinoma. Cancers (Basel), 2019, 11(8), 1-19.
[http://dx.doi.org/10.3390/cancers11081086] [PMID: 31370258]
[27]
Gerstner, E.R.; Eichler, A.F.; Plotkin, S.R.; Drappatz, J.; Doyle, C.L.; Xu, L.; Duda, D.G.; Wen, P.Y.; Jain, R.K.; Batchelor, T.T. Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide. J. Neurooncol., 2011, 103(2), 325-332.
[http://dx.doi.org/10.1007/s11060-010-0390-7] [PMID: 20821342]
[28]
Dika, I.E.; Abou-Alfa, G.K. Treatment options after sorafenib failure in patients with hepatocellular carcinoma. Clin. Mol. Hepatol., 2017, 23(4), 273-279.
[http://dx.doi.org/10.3350/cmh.2017.0108] [PMID: 29151326]
[29]
a) Drevs, J.; Siegert, P.; Medinger, M.; Mross, K.; Strecker, R.; Zirrgiebel, U.; Harder, J.; Blum, H.; Robertson, J.; Jürgensmeier, J.M.; Puchalski, T.A.; Young, H.; Saunders, O.; Unger, C. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J. Clin. Oncol., 2007, 25(21), 3045-3054.
[http://dx.doi.org/10.1200/JCO.2006.07.2066]
b) Alberts, S.R.; Fitch, T.R.; Kim, G.P.; Morlan, B.W.; Dakhil, S.R.; Gross, H.M.; Nair, S. Cediranib (AZD2171) in patients with advanced hepatocellular carcinoma: a phase II North Central Cancer Treatment Group Clinical Trial. J. Clin. Oncol., 2012, 35(4), 329-333.
[http://dx.doi.org/10.1097/COC.0b013e3182118cdf] [PMID: 21422991]
[30]
Noujaim, J.; Payne, L.S.; Judson, I.; Jones, R.L.; Huang, P.H. Phosphoproteomics in translational research: a sarcoma perspective. Ann. Oncol., 2016, 27(5), 787-794.
[http://dx.doi.org/10.1093/annonc/mdw030] [PMID: 26802162]
[31]
Yau, T.; Chen, P.J.; Chan, P.; Curtis, C.M.; Murphy, P.S.; Suttle, A.B.; Gauvin, J.; Hodge, J.P.; Dar, M.M.; Poon, R.T. Phase I dose-finding study of pazopanib in hepatocellular carcinoma: evaluation of early efficacy, pharmacokinetics, and pharmacodynamics. Clin. Cancer Res., 2011, 17(21), 6914-6923.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-0793] [PMID: 21831954]
[32]
Cranmer, L.D.; Loggers, E.T.; Pollack, S.M. Pazopanib in the management of advanced soft tissue sarcomas. Ther. Clin. Risk Manag., 2016, 12, 941-955.
[http://dx.doi.org/10.2147/TCRM.S84792] [PMID: 27354810]
[33]
Chow, A.K.; Yau, S.W.; Ng, L. Novel molecular targets in hepatocellular carcinoma. World J. Clin. Oncol., 2020, 11(8), 589-605.
[http://dx.doi.org/10.5306/wjco.v11.i8.589] [PMID: 32879846]
[34]
Park, J.W.; Finn, R.S.; Kim, J.S.; Karwal, M.; Li, R.K.; Ismail, F.; Thomas, M.; Harris, R.; Baudelet, C.; Walters, I.; Raoul, J.L. Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin. Cancer Res., 2011, 17(7), 1973-1983.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-2011] [PMID: 21349999]
[35]
Zhu, H.; Zhang, C.; Yang, X.; Yi, C. Treatment with Brivanib alaninate as a second-line monotherapy after Sorafenib failure in hepatocellular carcinoma: A case report. Medicine (Baltimore), 2019, 98(10), e14823.
[http://dx.doi.org/10.1097/MD.0000000000014823] [PMID: 30855507]
[36]
Kudo, M.; Cheng, A.L.; Park, J.W.; Park, J.H.; Liang, P.C.; Hidaka, H.; Izumi, N.; Heo, J.; Lee, Y.J.; Sheen, I.S.; Chiu, C.F.; Arioka, H.; Morita, S.; Arai, Y. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet Gastroenterol. Hepatol., 2018, 3(1), 37-46.
[http://dx.doi.org/10.1016/S2468-1253(17)30290-X] [PMID: 28988687]
[37]
Sousa, S.F.; Joana, S.R.; Leite, V. Sorafenib and sunitinib for the treatment of metastatic thyroid cancer of follicular origin: a 7-year single-centre experience. Eur. Thyroid J., 2019, 8(5), 262-267.
[http://dx.doi.org/10.1159/000501680] [PMID: 31768337]
[38]
Motzer, R.J.; Tannir, N.M.; McDermott, D.F.; Arén Frontera, O.; Melichar, B.; Choueiri, T.K.; Plimack, E.R.; Barthélémy, P.; Porta, C.; George, S.; Powles, T.; Donskov, F.; Neiman, V.; Kollmannsberger, C.K.; Salman, P.; Gurney, H.; Hawkins, R.; Ravaud, A.; Grimm, M.O.; Bracarda, S.; Barrios, C.H.; Tomita, Y.; Castellano, D.; Rini, B.I.; Chen, A.C.; Mekan, S.; McHenry, M.B.; Wind-Rotolo, M.; Doan, J.; Sharma, P.; Hammers, H.J.; Escudier, B. Nivolumab plus ipilimumab vs. sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med., 2018, 378(14), 1277-1290.
[http://dx.doi.org/10.1056/NEJMoa1712126] [PMID: 29562145]
[39]
Toh, H. Linifanib phase II trial in patients with advanced hepatocellular carcinoma (HCC). J. Clin. Oncol., 2010, 28(15), 4038.
[http://dx.doi.org/10.1200/jco.2010.28.15_suppl.4038]
[40]
Toh, H.C.; Chen, P.J.; Carr, B.I.; Knox, J.J.; Gill, S.; Ansell, P.; McKeegan, E.M.; Dowell, B.; Pedersen, M.; Qin, Q.; Qian, J.; Scappaticci, F.A.; Ricker, J.L.; Carlson, D.M.; Yong, W.P. Phase 2 trial of linifanib (ABT-869) in patients with unresectable or metastatic hepatocellular carcinoma. Cancer, 2013, 119(2), 380-387.
[http://dx.doi.org/10.1002/cncr.27758] [PMID: 22833179]
[41]
Bertino, G. Hepatocellular carcinoma: novel molecular targets in carcinogenesis for future therapies. Biomed. Res. Int., 2014, 2014, 203 693.
[42]
Zhu, A.X.; Kang, Y.K.; Yen, C.J.; Finn, R.S.; Galle, P.R.; Llovet, J.M.; Assenat, E.; Brandi, G.; Pracht, M.; Lim, H.Y.; Rau, K.M.; Motomura, K.; Ohno, I.; Merle, P.; Daniele, B.; Shin, D.B.; Gerken, G.; Borg, C.; Hiriart, J.B.; Okusaka, T.; Morimoto, M.; Hsu, Y.; Abada, P.B.; Kudo, M. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol., 2019, 20(2), 282-296.
[http://dx.doi.org/10.1016/S1470-2045(18)30937-9] [PMID: 30665869]
[43]
Wang, S.; Zhang, Z.; Peng, H.; Zeng, K. Recent advances on the roles of epidermal growth factor receptor in psoriasis. Am. J. Transl. Res., 2019, 11(2), 520-528.
[PMID: 30899359]
[44]
Arienti, C.; Pignatta, S.; Tesei, A. Epidermal growth factor receptor family and its role in gastric cancer. Front. Oncol., 2019, 9, 1308.
[http://dx.doi.org/10.3389/fonc.2019.01308] [PMID: 31850207]
[45]
Murphrey, M.B.; Varacallo, M.; Quaim, L. Biochemistry, epidermal growth factor receptor; stat pearls publishing, 2019.
[46]
Gumà, A.; Díaz-Sáez, F.; Camps, M.; Zorzano, A. Neuregulin, an effector on mitochondria metabolism that preserves insulin sensitivity. Front. Physiol., 2020, 11, 696.
[http://dx.doi.org/10.3389/fphys.2020.00696] [PMID: 32655416]
[47]
Dziadziuszko, R.; Jassem, J. Epidermal growth factor receptor (EGFR) inhibitors and derived treatments. Ann. Oncol., 2012, 23(10), 193-196.
[http://dx.doi.org/10.1093/annonc/mds351]
[48]
Liu, Z.; Lin, Y.; Zhang, J.; Zhang, Y.; Li, Y.; Liu, Z.; Li, Q.; Luo, M.; Liang, R.; Ye, J. Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma. J. Exp. Clin. Cancer Res., 2019, 38(1), 447.
[http://dx.doi.org/10.1186/s13046-019-1412-8] [PMID: 31684985]
[49]
Thomas, M.B.; Garrett-Mayer, E.; Anis, M.; Anderton, K.; Bentz, T.; Edwards, A.; Brisendine, A.; Weiss, G.; Siegel, A.B.; Bendell, J.; Baron, A.; Duddalwar, V.; El-Khoueiry, A. A randomized phase II open-label multi-institution study of the combination of bevacizumab and erlotinib compared to sorafenib in the first-line treatment of patients with advanced hepatocellular carcinoma. Oncology, 2018, 94(6), 329-339.
[http://dx.doi.org/10.1159/000485384] [PMID: 29719302]
[50]
Yamamoto, N.; Seto, T.; Nishio, M.; Goto, K.; Yamamoto, N.; Okamoto, I.; Yamanaka, T.; Tanaka, M.; Takahashi, K.; Fukuoka, M. Erlotinib plus bevacizumab vs erlotinib monotherapy as first- line treatment for advanced EGFR mutation-positive non-squamous non-small-cell lung cancer: Survival follow-up results of the randomized JO25567 study. Lung Cancer, 2021, 151, 20-24.
[http://dx.doi.org/10.1016/j.lungcan.2020.11.020] [PMID: 33279874]
[51]
Alves, R.C.P.; Alves, D.; Guz, B.; Matos, C.; Viana, M.; Harriz, M.; Terrabuio, D.; Kondo, M.; Gampel, O.; Polletti, P. Advanced hepatocellular carcinoma. Review of targeted molecular drugs. Ann. Hepatol., 2011, 10(1), 21-27.
[http://dx.doi.org/10.1016/S1665-2681(19)31582-0] [PMID: 21301005]
[52]
Nenu, I.; Breaban, I.; Pascalau, S.; Bora, C.N.; Stefanescu, H. The future is now: Beyond first line systemic therapy in hepatocellular carcinoma. Transl. Cancer Res., 2019, 8(6), S261-S274.
[http://dx.doi.org/10.21037/tcr.2018.11.23]
[53]
Daher, S.; Massarwa, M.; Benson, A.A.; Khoury, T. Current and future treatment of hepatocellular carcinoma: An updated comprehensive review. J. Clin. Transl. Hepatol., 2018, 6(1), 69-78.
[http://dx.doi.org/10.14218/JCTH.2017.00031] [PMID: 29607307]
[54]
Fan, X. Pre-diagnostic circulating concentrations of insulin-like growth factor-1 and risk of COVID-19 mortality: results from UK Biobank. Eur. J. Epidemiol, 36(3), 311-318.
[http://dx.doi.org/10.1101/2020.07.09.20149369]
[55]
Wu, J.; Zhu, A.X. Targeting insulin-like growth factor axis in hepatocellular carcinoma. J. Hematol Oncol, 4(1), 1-11.
[http://dx.doi.org/10.1186/1756-8722-4-30]
[56]
Tovar, V.; Alsinet, C.; Villanueva, A.; Hoshida, Y.; Chiang, D.Y.; Solé, M.; Thung, S.; Moyano, S.; Toffanin, S.; Mínguez, B.; Cabellos, L.; Peix, J.; Schwartz, M.; Mazzaferro, V.; Bruix, J.; Llovet, J.M. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J. Hepatol., 2010, 52(4), 550-559.
[http://dx.doi.org/10.1016/j.jhep.2010.01.015] [PMID: 20206398]
[57]
Simpson, A.; Petnga, W.; Macaulay, V.M.; Weyer-Czernilofsky, U.; Bogenrieder, T. Insulin-Like Growth Factor (IGF) pathway targeting in cancer: role of the IGF axis and opportunities for future combination studies. Target. Oncol., 2017, 12(5), 571-597.
[http://dx.doi.org/10.1007/s11523-017-0514-5] [PMID: 28815409]
[58]
Adamek, A.; Kasprzak, A. Insulin-like growth factor (IGF) system in liver diseases. Int. J. Mol. Sci., 2018, 19(5), 1-24.
[http://dx.doi.org/10.3390/ijms19051308] [PMID: 29702590]
[59]
Shirakawa, J.; Okuyama, T.; Yoshida, E.; Shimizu, M.; Horigome, Y.; Tuno, T.; Hayasaka, M.; Abe, S.; Fuse, M.; Togashi, Y.; Terauchi, Y. Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β- cell functions, and β-cell proliferation in male mice. Endocrinology, 2014, 155(6), 2102-2111.
[http://dx.doi.org/10.1210/en.2013-2032] [PMID: 24712877]
[60]
Fuentes-Baile, M.; Ventero, M.P.; Encinar, J.A.; García-Morales, P.; Poveda-Deltell, M.; Pérez-Valenciano, E.; Barberá, V.M.; Gallego-Plazas, J.; Rodríguez-Lescure, Á.; Martín-Nieto, J.; Saceda, M. Differential effects of IGF-1r small molecule tyrosine kinase inhibitors BMS-754807 and OSI-906 on human cancer cell lines. Cancers (Basel), 2020, 12(12), 3717.
[http://dx.doi.org/10.3390/cancers12123717] [PMID: 33322337]
[61]
Abou-Alfa, G.K. Phase II study of cixutumumab (IMC-A12, NSC742460; C) in hepatocellular carcinoma (HCC). J. Clin. Oncol., 2011, 29(15), 4043.
[http://dx.doi.org/10.1200/jco.2011.29.15_suppl.4043]
[62]
Li, L.; Zhao, G.D.; Shi, Z.; Qi, L.L.; Zhou, L.Y.; Fu, Z.X. The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncol. Lett., 2016, 12(5), 3045-3050.
[http://dx.doi.org/10.3892/ol.2016.5110] [PMID: 27899961]
[63]
Chung, E.; Kondo, M. Role of Ras/Raf/MEK/ERK signaling in physiological hematopoiesis and leukemia development. Immuno Res, 49(1-3), 248-268.
[http://dx.doi.org/10.1007/s12026-010-8187-5]
[64]
Chappell, W.H.; Steelman, L.S.; Long, J.M.; Kempf, R.C.; Abrams, S.L.; Franklin, R.A.; Bäsecke, J.; Stivala, F.; Donia, M.; Fagone, P.; Malaponte, G.; Mazzarino, M.C.; Nicoletti, F.; Libra, M.; Maksimovic-Ivanic, D.; Mijatovic, S.; Montalto, G.; Cervello, M.; Laidler, P.; Milella, M.; Tafuri, A.; Bonati, A.; Evangelisti, C.; Cocco, L.; Martelli, A.M.; McCubrey, J.A. Ras/Raf/MEK/ ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget, 2011, 2(3), 135-164.
[http://dx.doi.org/10.18632/oncotarget.240] [PMID: 21411864]
[65]
Wilhelm, S.M.; Adnane, L.; Newell, P.; Villanueva, A.; Llovet, J.M.; Lynch, M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther., 2008, 7(10), 3129-3140.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0013] [PMID: 18852116]
[66]
Parsons, H.M.; Chu, Q.; Karlitz, J.J.; Stevens, J.L.; Harlan, L.C. Adoption of sorafenib for the treatment of advanced-stage hepatocellular carcinoma in oncology practices in the United States. Liver Cancer, 2017, 6(3), 216-226.
[http://dx.doi.org/10.1159/000473862] [PMID: 29234628]
[67]
Liu, L.P.; Ho, R.L.K.; Chen, G.G.; Lai, P.B.S. Sorafenib inhibits hypoxia-inducible factor-1α synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. Clin. Cancer Res., 2012, 18(20), 5662-5671.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-0552] [PMID: 22929805]
[68]
Naito, S.; Ichiyanagi, O.; Ito, H.; Kabasawa, T.; Kanno, H.; Narisawa, T.; Fukuhara, H.; Yagi, M.; Kurota, Y.; Yamagishi, A.; Sakurai, T.; Nishida, H.; Kawazoe, H.; Yamanobe, T.; Kato, T.; Makhov, P.; Kolenko, V.M.; Yamakawa, M.; Tsuchiya, N. Expression of total and phospho 4EBP1 in metastatic and non-metastatic renal cell carcinoma. Oncol. Lett., 2019, 17(4), 3910-3918.
[http://dx.doi.org/10.3892/ol.2019.10033] [PMID: 30881508]
[69]
Dudgeon, C.; Peng, R.; Wang, P.; Sebastiani, A.; Yu, J.; Zhang, L. Inhibiting oncogenic signaling by sorafenib activates PUMA via GSK3β and NF-κB to suppress tumor cell growth. Oncogene, 2012, 31(46), 4848-4858.
[http://dx.doi.org/10.1038/onc.2011.644] [PMID: 22286758]
[70]
Abraham, A.; Purushothaman, C.; Damien, D.; James, J.; Rodrigues, P.A.; Singh, G. Efficacy of sorafenib therapy in patients with advanced hepatocellular carcinoma in Indian population. Hepatoma Res., 2016, 2(8), 224.
[http://dx.doi.org/10.20517/2394/5079.2016.03]
[71]
Kim, J.E.; Ryoo, B.Y.; Ryu, M.H.; Chang, H.M.; Suh, D.J.; Lee, H.C.; Lim, Y.S.; Kim, K.M.; Kang, Y.K. Sorafenib for hepatocellular carcinoma according to Child-Pugh class of liver function. Cancer Chemother. Pharmacol., 2011, 68(5), 1285-1290.
[http://dx.doi.org/10.1007/s00280-011-1616-x] [PMID: 21445543]
[72]
Hollebecque, A.; Cattan, S.; Romano, O.; Sergent, G.; Mourad, A.; Louvet, A.; Dharancy, S.; Boleslawski, E.; Truant, S.; Pruvot, F.R.; Hebbar, M.; Ernst, O.; Mathurin, P. Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score. Aliment. Pharmacol. Ther., 2011, 34(10), 1193-1201.
[http://dx.doi.org/10.1111/j.1365-2036.2011.04860.x] [PMID: 21958438]
[73]
Dufour, J-F.; Hoppe, H.; Heim, M.H.; Helbling, B.; Maurhofer, O.; Szucs-Farkas, Z.; Kickuth, R.; Borner, M.; Candinas, D.; Saar, B. Continuous administration of sorafenib in combination with transarterial chemoembolization in patients with hepatocellular carcinoma: results of a phase I study. Oncologist, 2010, 15(11), 1198-1204.
[http://dx.doi.org/10.1634/theoncologist.2010-0180] [PMID: 21036880]
[74]
Abou-Alfa, G.K.; Johnson, P.; Knox, J.J.; Capanu, M.; Davidenko, I.; Lacava, J.; Leung, T.; Gansukh, B.; Saltz, L.B. Doxorubicin plus sorafenib vs. doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA, 2010, 304(19), 2154-2160.
[http://dx.doi.org/10.1001/jama.2010.1672] [PMID: 21081728]
[75]
Bolondi, L.; Gramantieri, L. From liver cirrhosis to HCC. Intern. Emerg. Med., 2011, 6(S1)(Suppl. 1), 93-98.
[http://dx.doi.org/10.1007/s11739-011-0682-8] [PMID: 22009618]
[76]
Bruix, J.; Tak, W.Y.; Gasbarrini, A.; Santoro, A.; Colombo, M.; Lim, H.Y.; Mazzaferro, V.; Wiest, R.; Reig, M.; Wagner, A.; Bolondi, L. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur. J. Cancer, 2013, 49(16), 3412-3419.
[http://dx.doi.org/10.1016/j.ejca.2013.05.028] [PMID: 23809766]
[77]
Bruix, J.; Qin, S.; Merle, P.; Granito, A.; Huang, Y.H.; Bodoky, G.; Pracht, M.; Yokosuka, O.; Rosmorduc, O.; Breder, V.; Gerolami, R.; Masi, G.; Ross, P.J.; Song, T.; Bronowicki, J.P.; Ollivier-Hourmand, I.; Kudo, M.; Cheng, A.L.; Llovet, J.M.; Finn, R.S.; LeBerre, M.A.; Baumhauer, A.; Meinhardt, G.; Han, G. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 389(10064), 56-66.
[http://dx.doi.org/10.1016/S0140-6736(16)32453-9] [PMID: 27932229]
[78]
Roskoski, R., Jr Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update. Pharmacol. Res., 2021, 165, 105463.
[http://dx.doi.org/10.1016/j.phrs.2021.105463] [PMID: 33513356]
[79]
Pacey, S. A phase I dose escalation study of the tolerability of the oral VEGFR and EGFR inhibitor vandetanib in combination with the oral MEK1/2 inhibitor selumetinib in solid tumors. Ann. Oncol., 2016, 27(6), v1437.
[http://dx.doi.org/10.1093/annonc/mdw383.61]
[80]
Xie, Y.; Shi, X.; Sheng, K.; Han, G.; Li, W.; Zhao, Q.; Jiang, B.; Feng, J.; Li, J.; Gu, Y. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol. Med. Rep., 2019, 19(2), 783-791.
[http://dx.doi.org/10.3892/mmr.2018.9713] [PMID: 30535469]
[81]
Xu, F.; Na, L.; Li, Y.; Chen, L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci., 10, 1-12.
[http://dx.doi.org/10.1186/s13578-020-00416-0]
[82]
Keppler-Noreuil, K.M.; Parker, V.E.R.; Darling, T.N.; Martinez-Agosto, J.A. Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies. Am. J. Med. Genet., 172(4), 402-421.
[http://dx.doi.org/10.1002/ajmg.c.31531]
[83]
Asahina, H.; Nokihara, H.; Yamamoto, N.; Yamada, Y.; Tamura, Y.; Honda, K.; Seki, Y.; Tanabe, Y.; Shimada, H.; Shi, X.; Tamura, T. Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; a dose-finding phase I study. Invest. New Drugs, 2013, 31(3), 677-684.
[http://dx.doi.org/10.1007/s10637-012-9860-4] [PMID: 22843211]
[84]
Finn, R.S. Current and future treatment strategies for patients with advanced hepatocellular carcinoma: role of mTOR inhibition. Liver Cancer, 2012, 1(3-4), 247-256.
[http://dx.doi.org/10.1159/000343839] [PMID: 24159589]
[85]
Geissler, E.K.; Schnitzbauer, A.A.; Zülke, C.; Lamby, P.E.; Proneth, A.; Duvoux, C.; Burra, P.; Jauch, K-W.; Rentsch, M.; Ganten, T.M.; Schmidt, J.; Settmacher, U.; Heise, M.; Rossi, G.; Cillo, U.; Kneteman, N.; Adam, R.; van Hoek, B.; Bachellier, P.; Wolf, P.; Rostaing, L.; Bechstein, W.O.; Rizell, M.; Powell, J.; Hidalgo, E.; Gugenheim, J.; Wolters, H.; Brockmann, J.; Roy, A.; Mutzbauer, I.; Schlitt, A.; Beckebaum, S.; Graeb, C.; Nadalin, S.; Valente, U.; Turrión, V.S.; Jamieson, N.; Scholz, T.; Colledan, M.; Fändrich, F.; Becker, T.; Söderdahl, G.; Chazouillères, O.; Mäkisalo, H.; Pageaux, G-P.; Steininger, R.; Soliman, T.; Jong, K.P.; Pirenne, J.; Margreiter, R.; Pratschke, J.; Pinna, A.D.; Hauss, J.; Schreiber, S.; Strasser, S.; Klempnauer, J.; Troisi, R.; Bhoori, S.; Lerut, J.; Bilbao, I.; Klein, C.G.; Königsrainer, A.; Mirza, D.F.; Otto, G.; Mazzaferro, V.; Neuhaus, P.; Schlitt, H. Sirolimus use in liver transplant recipients with hepatocellular carcinoma-A randomized, multicenter, open-label phase 3 trial. Transplantation, 2016, 100(1), 116-125.
[http://dx.doi.org/10.1097/TP.0000000000000965]
[86]
Kasprzak, A. Angiogenesis-related functions of WNT signaling in colorectal carcinogenesis. Cancers (Basel), 2020, 12(12), 3601.
[http://dx.doi.org/10.3390/cancers12123601]
[87]
Herencia, C.; Martínez-Moreno, J.M.; Herrera, C.; Corrales, F.; Santiago-Mora, R. pone.0034656 1.13. Nuclear translocation of β- catenin during mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype. PLoS One, 2012, 7(4), 34656.
[http://dx.doi.org/10.1371/journal.pone.0034656] [PMID: 22506042]
[88]
Wei, W.; Chua, M-S.; Grepper, S.; So, S. Small molecule antagonists of Tcf4/Î2-catenin complex inhibit the growth of HCC cells in vitro and in vivo. Int. J. Cancer, 2010, 126(10), 2426-2436.
[http://dx.doi.org/10.1002/ijc.24810] [PMID: 19662654]
[89]
Wils, L.J.; Bijlsma, M.F. Epigenetic regulation of the Hedgehog and Wnt pathways in cancer. Crit. Rev. Oncol. Hematol., 121, 23-44.
[http://dx.doi.org/10.1016/j.critrevonc.2017.11.013]
[90]
Della Corte, C.M.; Viscardi, G.; Papaccio, F.; Esposito, G.; Martini, G.; Ciardiello, D.; Martinelli, E.; Ciardiello, F.; Morgillo, F. Implication of the Hedgehog pathway in hepatocellular carcinoma. World J. Gastroenterol., 2017, 23(24), 4330-4340.
[http://dx.doi.org/10.3748/wjg.v23.i24.4330] [PMID: 28706416]
[91]
Whittaker, S.; Marais, R.; Zhu, A.X. The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene, 2010, 29, 4989-5005.
[http://dx.doi.org/10.1038/onc.2010.236]
[92]
Moeini, A.; Cornellà, H.; Villanueva, A. Emerging signaling pathways in hepatocellular carcinoma. Liver Cancer, 2012, 1(2), 83-93.
[http://dx.doi.org/10.1159/000342405] [PMID: 24159576]
[93]
Borbath, I. Randomized Controlled Phase 2 Study (RCT) with Tivantinib in pre-treated hepatocellular carcinoma (HCC): Efficacy, Safety, and MET-analysis. Hepatology, 2012, 56, 250A.
[94]
Oura, K.; Morishita, A.; Masaki, T. Molecular and functional roles of microRNAs in the progression of hepatocellular carcinoma-A review. Int. J. Mol. Sci., 21(21), 1-30.
[http://dx.doi.org/10.3390/ijms21218362]
[95]
Llovet, J.M. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol., 2012, 56(4), 908-943.
[http://dx.doi.org/10.1016/j.jhep.2011.12.001] [PMID: 22424438]
[96]
Qin, T.; Liu, H.; Song, Q.; Song, G.; Wang, H.Z.; Pan, Y.Y.; Xiong, F.X.; Gu, K.S.; Sun, G.P.; Chen, Z.D. The screening of volatile markers for hepatocellular carcinoma. Cancer Epidemiol. Biomarkers Prev., 2010, 19(9), 2247-2253.
[http://dx.doi.org/10.1158/1055-9965.EPI-10-0302] [PMID: 20826831]
[97]
Slotta, J.E.; Kollmar, O.; Ellenrieder, V.; Ghadimi, B.M.; Homayounfar, K. Hepatocellular carcinoma: Surgeon’s view on latest findings and future perspectives. World J. Hepatol., 2015, 7(9), 1168-1183.
[http://dx.doi.org/10.4254/wjh.v7.i9.1168] [PMID: 26019733]
[98]
Mokbel, K.; Wazir, U.; Mokbel, K. Chemoprevention of prostate cancer by natural agents: Evidence from molecular and epidemiological studies. Anticancer Res., 2019, 39(10), 5231-5259.
[http://dx.doi.org/10.21873/anticanres.13720] [PMID: 31570421]
[99]
Yau, H.; Kinaan, M.; Quinn, S.L.; Moraitis, A.G. Octreotide long-acting repeatable in the treatment of neuroendocrine tumors: Patient selection and perspectives. Biol. Targets Ther., 2017, 11, 115-122.
[http://dx.doi.org/10.2147/BTT.S108818]
[100]
Greten, T.F.; Duffy, A.G.; Korangy, F. Hepatocellular carcinoma from an immunologic perspective. Clin. Cancer Res., 2013, 19(24), 6678-6685.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-1721] [PMID: 24030702]
[101]
Da Fonseca, L.G.; Carrilho, F.J. Updates in immunotherapy for hepatocellular carcinoma. Hepatoma Res., 2019, 2019
[http://dx.doi.org/10.20517/2394/5079.2019.012]
[102]
Li, Y.; Martin, R.C.G., II. Herbal medicine and hepatocellular carcinoma: applications and challenges. Evid. Based Complement. Alternat. Med., 2011, 2011, 541209.
[http://dx.doi.org/10.1093/ecam/neq044] [PMID: 21799681]
[103]
Rasool, M.; Rashid, S.; Arooj, M.; Ansari, S.A.; Khan, K.M.; Malik, A.; Naseer, M.I.; Zahid, S.; Manan, A.; Asif, M.; Razzaq, Z.; Ashraf, S.; Qazi, M.H.; Iqbal, Z.; Gan, S.H.; Kamal, M.A.; Sheikh, I.A. New possibilities in hepatocellular carcinoma treatment. Anticancer Res., 2014, 34(4), 1563-1571.
[PMID: 24692683]
[104]
Abou-Alfa, G.K. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med., 2018, 379(1), 54-63.
[http://dx.doi.org/10.1056/NEJMoa1717002]
[105]
El-Khoueiry, A.B.; Sangro, B.; Yau, T.; Crocenzi, T.S.; Kudo, M.; Hsu, C.; Kim, T.Y.; Choo, S.P.; Trojan, J.; Welling, T.H.; Meyer, T.; Kang, Y.K.; Yeo, W.; Chopra, A.; Anderson, J.; Dela Cruz, C.; Lang, L.; Neely, J.; Tang, H.; Dastani, H.B.; Melero, I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet, 2017, 389(10088), 2492-2502.
[http://dx.doi.org/10.1016/S0140-6736(17)31046-2] [PMID: 28434648]
[106]
Zhu, A.X.; Finn, R.S.; Edeline, J.; Cattan, S.; Ogasawara, S.; Palmer, D.; Verslype, C.; Zagonel, V.; Fartoux, L.; Vogel, A.; Sarker, D.; Verset, G.; Chan, S.L.; Knox, J.; Daniele, B.; Webber, A.L.; Ebbinghaus, S.W.; Ma, J.; Siegel, A.B.; Cheng, A.L.; Kudo, M. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol., 2018, 19(7), 940-952.
[http://dx.doi.org/10.1016/S1470-2045(18)30351-6] [PMID: 29875066]
[107]
Zhou, J.; Sun, H.C.; Wang, Z.; Cong, W.M.; Wang, J.H.; Zeng, M.S.; Yang, J.M.; Bie, P.; Liu, L.X.; Wen, T.F.; Han, G.H.; Wang, M.Q.; Liu, R.B.; Lu, L.G.; Ren, Z.G.; Chen, M.S.; Zeng, Z.C.; Liang, P.; Liang, C.H.; Chen, M.; Yan, F.H.; Wang, W.P.; Ji, Y.; Cheng, W.W.; Dai, C.L.; Jia, W.D.; Li, Y.M.; Li, Y.X.; Liang, J.; Liu, T.S.; Lv, G.Y.; Mao, Y.L.; Ren, W.X.; Shi, H.C.; Wang, W.T.; Wang, X.Y.; Xing, B.C.; Xu, J.M.; Yang, J.Y.; Yang, Y.F.; Ye, S.L.; Yin, Z.Y.; Zhang, B.H.; Zhang, S.J.; Zhou, W.P.; Zhu, J.Y.; Liu, R.; Shi, Y.H.; Xiao, Y.S.; Dai, Z.; Teng, G.J.; Cai, J.Q.; Wang, W.L.; Dong, J.H.; Li, Q.; Shen, F.; Qin, S.K.; Fan, J. Guidelines for diagnosis and treatment of primary liver cancer in China (2017 edition). Liver Cancer, 2018, 7(3), 235-260.
[http://dx.doi.org/10.1159/000488035] [PMID: 30319983]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy