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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Mini-Review Article

Advancements in Hepatocellular Carcinoma: Potential Preclinical Drugs and their Future

Author(s): Noor-ul-Huda Butt and Sultan Nacak Baytas*

Volume 29, Issue 1, 2023

Published on: 29 December, 2022

Page: [2 - 14] Pages: 13

DOI: 10.2174/1381612829666221216114350

Price: $65

Abstract

Hepatocellular carcinoma (HCC) is one of the foremost causes of tumor-affiliated demises globally. The HCC treatment has undergone numerous developments in terms of both drug and non-drug treatments. The United States Food and Drug Administration (FDA) has authorized the usage of a variety of drugs for the treatment of HCC in recent years, involving multi-kinase inhibitors (lenvatinib, regorafenib, ramucirumab, and cabozantinib), immune checkpoint inhibitors (ICIs) (pembrolizumab and nivolumab), and combination therapies like atezolizumab along with bevacizumab. There are currently over a thousand ongoing clinical and preclinical studies for novel HCC drugs, which portrays a competent setting in the field. This review discusses the i. FDA-approved HCC drugs, their molecular targets, safety profiles, and potential disadvantages; ii. The intrial agents/drugs, their molecular targets, and possible benefits compared to alternatives, and iii. The current and future status of potential preclinical drugs with novel therapeutic targets for HCC. Consequently, existing drug treatments and novel strategies with their balanced consumption could ensure a promising future for a universal remedy of HCC in the near future.

[1]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Schlabe S, Rockstroh JK. Advances in the treatment of HIV/HCV coinfection in adults. Expert Opin Pharmacother 2018; 19(1): 49-64.
[http://dx.doi.org/10.1080/14656566.2017.1419185] [PMID: 29252031]
[3]
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet 2015; 386(10003): 1546-55.
[http://dx.doi.org/10.1016/S0140-6736(15)61412-X] [PMID: 26231459]
[4]
Sacco R, Tapete G, Simonetti N, et al. Transarterial chemoembolization for the treatment of hepatocellular carcinoma: a review. J Hepatocell Carcinoma 2017; 4: 105-10.
[http://dx.doi.org/10.2147/JHC.S103661] [PMID: 28795053]
[5]
Zhang Q, He Y, Luo N, et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 2019; 179(4): 829-845.e20.
[http://dx.doi.org/10.1016/j.cell.2019.10.003] [PMID: 31675496]
[6]
Luo XY, Wu KM, He XX. Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets. J Exp Clin Cancer Res 2021; 40(1): 172.
[http://dx.doi.org/10.1186/s13046-021-01968-w] [PMID: 34006331]
[7]
Cervello M, Bachvarov D, Lampiasi N, et al. Molecular mechanisms of sorafenib action in liver cancer cells. Cell Cycle 2012; 11(15): 2843-55.
[http://dx.doi.org/10.4161/cc.21193] [PMID: 22801548]
[8]
Sun W, He B, Yang B, et al. Genome-wide CRISPR screen reveals SGOL1 as a druggable target of sorafenib-treated hepatocellular carcinoma. Lab Invest 2018; 98(6): 734-44.
[http://dx.doi.org/10.1038/s41374-018-0027-6] [PMID: 29467456]
[9]
Mary YS, Mary YS, Rad AS, Yadav R, Celik I, Sarala S. Theoretical investigation on the reactive and interaction properties of sorafenib - DFT, AIM, spectroscopic and Hirshfeld analysis, docking and dynamics simulation. J Mol Liq 2021; 330: 115652.
[http://dx.doi.org/10.1016/j.molliq.2021.115652]
[10]
Dawkins J, Webster RM. The hepatocellular carcinoma market. Nat Rev Drug Discov 2019; 18(1): 13-4.
[http://dx.doi.org/10.1038/nrd.2018.146] [PMID: 30168534]
[11]
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359(4): 378-90.
[http://dx.doi.org/10.1056/NEJMoa0708857] [PMID: 18650514]
[12]
Bruix J, Cheng AL, Meinhardt G, Nakajima K, De Sanctis Y, Llovet J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies. J Hepatol 2017; 67(5): 999-1008.
[http://dx.doi.org/10.1016/j.jhep.2017.06.026] [PMID: 28687477]
[13]
McNamara MG, Slagter AE, Nuttall C, et al. Sorafenib as first- line therapy in patients with advanced child-pugh B hepatocellular carcinoma-A meta-analysis. Eur J Cancer 2018; 105: 1-9.
[http://dx.doi.org/10.1016/j.ejca.2018.09.031] [PMID: 30384012]
[14]
Kudo M, Ueshima K, Yokosuka O, et al. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. Lancet Gastroenterol Hepatol 2018; 3(6): 424-32.
[http://dx.doi.org/10.1016/S2468-1253(18)30078-5] [PMID: 29631810]
[15]
Lencioni R, Kudo M, Ye SL, et al. GIDEON (global investigation of therapeutic DE cisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis. Int J Clin Pract 2014; 68(5): 609-17.
[http://dx.doi.org/10.1111/ijcp.12352] [PMID: 24283303]
[16]
El-Khoueiry AB, Sangro B, Yau T, et al. 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): 2492-502.
[http://dx.doi.org/10.1016/S0140-6736(17)31046-2] [PMID: 28434648]
[17]
Picardo SL, Doi J, Hansen AR. Structure and optimization of checkpoint inhibitors. Cancers 2019; 12(1): 38.
[http://dx.doi.org/10.3390/cancers12010038] [PMID: 31877721]
[18]
Al-Salama ZT, Syed YY, Scott LJ. Lenvatinib: A review in hepatocellular carcinoma. Drugs 2019; 79(6): 665-74.
[http://dx.doi.org/10.1007/s40265-019-01116-x] [PMID: 30993651]
[19]
Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res 2014; 2014: 1-13.
[http://dx.doi.org/10.1155/2014/638747] [PMID: 25295214]
[20]
Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet 2018; 391(10126): 1163-73.
[http://dx.doi.org/10.1016/S0140-6736(18)30207-1] [PMID: 29433850]
[21]
Suyama K, Iwase H. Lenvatinib. Cancer Contr 2018; 25(1)
[http://dx.doi.org/10.1177/1073274818789361] [PMID: 30032643]
[22]
Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020; 382(20): 1894-905.
[http://dx.doi.org/10.1056/NEJMoa1915745] [PMID: 32402160]
[23]
Greten TF, Lai CW, Li G, Staveley-O’Carroll KF. Targeted and immune-based therapies for hepatocellular carcinoma. Gastroenterology 2019; 156(2): 510-24.
[http://dx.doi.org/10.1053/j.gastro.2018.09.051] [PMID: 30287171]
[24]
Iwamoto H, Shimose S, Noda Y, et al. Initial experience of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in real-world clinical practice. Cancers 2021; 13(11): 2786.
[http://dx.doi.org/10.3390/cancers13112786] [PMID: 34205099]
[25]
Bruix J, Qin S, Merle P, et al. 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]
[26]
Ettrich TJ, Seufferlein T. Regorafenib. Recent Results Cancer Res 2018; 211: 45-56.
[http://dx.doi.org/10.1007/978-3-319-91442-8_3] [PMID: 30069758]
[27]
Shlomai A, Leshno M, Goldstein DA. Regorafenib treatment for patients with hepatocellular carcinoma who progressed on sorafenib-A cost-effectiveness analysis. PLoS One 2018; 13(11): e0207132.
[http://dx.doi.org/10.1371/journal.pone.0207132] [PMID: 30408106]
[28]
Zhu AX, Park JO, Ryoo BY, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): A randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2015; 16(7): 859-70.
[http://dx.doi.org/10.1016/S1470-2045(15)00050-9] [PMID: 26095784]
[29]
Cooper M, Binkowski C, Hartung J, Towle J. Profile of ramucirumab in the treatment of metastatic non-small-cell lung cancer. OncoTargets and Therapy 2016; 1953.
[http://dx.doi.org/10.2147/OTT.S80239]
[30]
Zhu AX, Baron AD, Malfertheiner P, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma. JAMA Oncol 2017; 3(2): 235-43.
[http://dx.doi.org/10.1001/jamaoncol.2016.4115] [PMID: 27657674]
[31]
Zheng H, Qin Z, Qiu X, Zhan M, Wen F, Xu T. Cost-effectiveness analysis of ramucirumab treatment for patients with hepatocellular carcinoma who progressed on sorafenib with α-fetoprotein concentrations of at least 400 ng/ml. J Med Econ 2020; 23(4): 347-52.
[http://dx.doi.org/10.1080/13696998.2019.1707211] [PMID: 31856618]
[32]
Cochin V, Gross-Goupil M, Ravaud A, Godbert Y, Le Moulec S. Cabozantinib : modes of action, efficacy and indications. Bull Cancer 2017; 104(5): 393-401.
[http://dx.doi.org/10.1016/j.bulcan.2017.03.013] [PMID: 28477875]
[33]
Xiang Q, Chen W, Ren M, et al. Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET. Clin Cancer Res 2014; 20(11): 2959-70.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-2620] [PMID: 24700742]
[34]
Abou-Alfa GK, Meyer T, Cheng AL, et al. 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] [PMID: 29972759]
[35]
Nguyen L, Chapel S, Tran BD, Lacy S. Cabozantinib exposure–response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma. J Pharmacokinet Pharmacodyn 2019; 46(6): 577-89.
[http://dx.doi.org/10.1007/s10928-019-09659-y] [PMID: 31637577]
[36]
Zhu AX, Finn RS, Edeline J, et al. 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): 940-52.
[http://dx.doi.org/10.1016/S1470-2045(18)30351-6] [PMID: 29875066]
[37]
Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: A randomized, double-blind, phase III trial. J Clin Oncol 2020; 38(3): 193-202.
[http://dx.doi.org/10.1200/JCO.19.01307] [PMID: 31790344]
[38]
Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. JAMA Oncol 2020; 6(11): e204564.
[http://dx.doi.org/10.1001/jamaoncol.2020.4564] [PMID: 33001135]
[39]
Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018; 36(8): 773-9.
[http://dx.doi.org/10.1200/JCO.2017.76.9901] [PMID: 29355075]
[40]
Chen Z, Xie H, Hu M, et al. Recent progress in treatment of hepatocellular carcinoma. Am J Cancer Res 2020; 10(9): 2993-3036.
[PMID: 33042631]
[41]
Llovet JM, Di Bisceglie AM, Bruix J, et al. Trials ftPoEiH-DC. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698-711.
[http://dx.doi.org/10.1093/jnci/djn134] [PMID: 18477802]
[42]
Chow LQM, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007; 25(7): 884-96.
[http://dx.doi.org/10.1200/JCO.2006.06.3602] [PMID: 17327610]
[43]
Toh HC, Chen PJ, Carr BI, et al. Phase 2 trial of linifanib (ABT-869) in patients with unresectable or metastatic hepatocellular carcinoma. Cancer 2013; 119(2): 380-7.
[http://dx.doi.org/10.1002/cncr.27758] [PMID: 22833179]
[44]
Yen CJ, Kim TY, Feng YH, et al. A phase I/randomized phase II study to evaluate the safety, pharmacokinetics, and efficacy of nintedanib versus sorafenib in Asian patients with advanced hepatocellular carcinoma. Liver Cancer 2018; 7(2): 165-78.
[http://dx.doi.org/10.1159/000486460] [PMID: 29888206]
[45]
Liu J, Li X, Zhang H, et al. Safety, pharmacokinetics and efficacy of donafenib in treating advanced hepatocellular carcinoma: report from a phase 1b trial. Pharmazie 2019; 74(11): 688-93.
[PMID: 31739839]
[46]
Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66(2): 115-32.
[http://dx.doi.org/10.3322/caac.21338] [PMID: 26808342]
[47]
Qiao L, Xu Z, Zhao T, et al. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res 2008; 18(4): 500-7.
[http://dx.doi.org/10.1038/cr.2008.40] [PMID: 18364678]
[48]
Luo Y, Lin C, Ren W, et al. Intravenous injections of a rationally selected oncolytic herpes virus as a potent virotherapy for hepatocellular carcinoma. Mol Ther Oncolytics 2019; 15: 153-65.
[http://dx.doi.org/10.1016/j.omto.2019.09.004] [PMID: 31720372]
[49]
Yu LX, Yan HX, Liu Q, et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 2010; 52(4): 1322-33.
[http://dx.doi.org/10.1002/hep.23845] [PMID: 20803560]
[50]
Starokozhko V, Groothuis GMM. Challenges on the road to a multicellular bioartificial liver. J Tissue Eng Regen Med 2018; 12(1): e227-36.
[http://dx.doi.org/10.1002/term.2385] [PMID: 27943623]
[51]
Nakatsura T, Yoshitake Y, Senju S, et al. Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. Biochem Biophys Res Commun 2003; 306(1): 16-25.
[http://dx.doi.org/10.1016/S0006-291X(03)00908-2] [PMID: 12788060]
[52]
Fang T, Zhao Z, Yuan F, et al. Actinidia chinensis planch root extract attenuates proliferation and metastasis of hepatocellular carcinoma by inhibiting the DLX2/TARBP2/JNK/AKT pathway. J Ethnopharmacol 2020; 251: 112529.
[http://dx.doi.org/10.1016/j.jep.2019.112529] [PMID: 31891797]
[53]
Huang Y, Liu C, Zeng WC, et al. Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway. Biosci Rep 2020; 40(1): BSR20192727.
[http://dx.doi.org/10.1042/BSR20192727] [PMID: 31840737]
[54]
Chou LF, Chen CY, Yang WH, et al. Suppression of hepatocellular carcinoma progression through FOXM1 and EMT Inhibition via hydroxygenkwanin-induced miR-320a expression. Biomolecules 2019; 10(1): 20.
[http://dx.doi.org/10.3390/biom10010020] [PMID: 31877715]
[55]
Su Q, Fan M, Wang J, et al. Sanguinarine inhibits epithelial–mesenchymal transition via targeting HIF-1α/TGF-β feed-forward loop in hepatocellular carcinoma. Cell Death Dis 2019; 10(12): 939.
[http://dx.doi.org/10.1038/s41419-019-2173-1]
[56]
Sun R, Zhai R, Ma C, Miao W. Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway. Cancer Med 2020; 9(3): 1141-51.
[http://dx.doi.org/10.1002/cam4.2723] [PMID: 31830378]
[57]
Gnocchi D, Kapoor S, Nitti P, et al. Novel lysophosphatidic acid receptor 6 antagonists inhibit hepatocellular carcinoma growth through affecting mitochondrial function. J Mol Med 2020; 98(2): 179-91.
[http://dx.doi.org/10.1007/s00109-019-01862-1] [PMID: 31863151]
[58]
Peddibhotla S, Hershberger PM, Jason Kirby R, et al. Discovery of small molecule antagonists of chemokine receptor CXCR6 that arrest tumor growth in SK-HEP-1 mouse xenografts as a model of hepatocellular carcinoma. Bioorg Med Chem Lett 2020; 30(4): 126899.
[http://dx.doi.org/10.1016/j.bmcl.2019.126899] [PMID: 31882297]
[59]
Zigmond E, Ya’acov AB, Lee H, et al. Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase. ACS Med Chem Lett 2015; 6(8): 840-4.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00153] [PMID: 26288681]
[60]
Silverman RB. Inactivators of ornithine aminotransferase for the treatment of hepatocellular carcinoma. ACS Med Chem Lett 2022; 13(1): 38-49.
[http://dx.doi.org/10.1021/acsmedchemlett.1c00526] [PMID: 35059122]
[61]
Jennemann R, Federico G, Mathow D, et al. Inhibition of hepatocellular carcinoma growth by blockade of glycosphingolipid synthesis. Oncotarget 2017; 8(65): 109201-16.
[http://dx.doi.org/10.18632/oncotarget.22648] [PMID: 29312601]
[62]
Su T, Qin XY, Dohmae N, et al. Inhibition of ganglioside synthesis suppressed liver cancer cell proliferation through targeting kinetochore metaphase signaling. Metabolites 2021; 11(3): 167.
[http://dx.doi.org/10.3390/metabo11030167] [PMID: 33803928]
[63]
Zhao X, Ogunwobi OO, Liu C. Survivin inhibition is critical for Bcl-2 inhibitor-induced apoptosis in hepatocellular carcinoma cells. PLoS One 2011; 6(8): e21980.
[http://dx.doi.org/10.1371/journal.pone.0021980] [PMID: 21829603]
[64]
Zhang B, Wang N, Zhang C, et al. Novel multi-substituted benzyl acridone derivatives as survivin inhibitors for hepatocellular carcinoma treatment. Eur J Med Chem 2017; 129: 337-48.
[http://dx.doi.org/10.1016/j.ejmech.2017.02.027] [PMID: 28237663]
[65]
Xing X, Yuan H, Liu H, et al. Quantitative secretome analysis reveals clinical values of carbonic anhydrase ii in hepatocellular carcinoma. Genomics Proteomics Bioinformatics 2021; 19(1): 94-107.
[http://dx.doi.org/10.1016/j.gpb.2020.09.005] [PMID: 33662630]
[66]
Sayed MM, Soliman ML, Tamim YM, Osman AH, Hussain MSA-R. Potential anti-carcinogenic effect of acetazolamide, a carbonic anhydrase enzyme inhibitor, in diethylnitrosamine - induced hepatocarcinogenesis in rats. Int J Med 2021; 114.
[67]
Garmpis N, Damaskos C, Garmpi A, et al. Histone deacetylase inhibitors in the treatment of hepatocellular carcinoma: current evidence and future opportunities. J Pers Med 2021; 11(3): 223.
[http://dx.doi.org/10.3390/jpm11030223] [PMID: 33809844]
[68]
Loong HH, Yeo W. Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma. Onco Targets Ther 2014; 7: 575-85.
[PMID: 24790457]
[69]
Yang M, Su Y, Wang Z, et al. C118P, a novel microtubule inhibitor with anti-angiogenic and vascular disrupting activities, exerts anti-tumor effects against hepatocellular carcinoma. Biochem Pharmacol 2021; 190: 114641.
[http://dx.doi.org/10.1016/j.bcp.2021.114641] [PMID: 34077738]
[70]
Yan J, Zhuang Q, Li Z, et al. MIL-1, a novel antitumor agent derived from natural product millepachine, acts as tubulin polymerization inhibitor for the treatment of hepatocellular carcinoma. Eur J Pharmacol 2021; 898: 173975.
[http://dx.doi.org/10.1016/j.ejphar.2021.173975] [PMID: 33647258]
[71]
Shek D, Read SA, Nagrial A, et al. Immune-checkpoint inhibitors for advanced hepatocellular carcinoma: A synopsis of response rates. Oncologist 2021; 26(7): e1216-25.
[http://dx.doi.org/10.1002/onco.13776] [PMID: 33818870]
[72]
Oranratnachai S, Rattanasiri S, Pooprasert A, et al. Efficacy of first line systemic chemotherapy and multikinase inhibitors in advanced hepatocellular carcinoma: A systematic review and network meta-analysis. Front Oncol 2021; 11: 654020.
[http://dx.doi.org/10.3389/fonc.2021.654020] [PMID: 33869060]
[73]
Kanzaki H, Chiba T, Ao J, et al. The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma. Sci Rep 2021; 11(1): 5303.
[http://dx.doi.org/10.1038/s41598-021-84117-9] [PMID: 33674622]

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