Molecular Pathogenesis and Targeted Therapy of Hepatocellular Carcinoma

Review Article · Übersichtsarbeit

Onkologie 2008;31:550–555 Published online: September 9, 2008

DOI: 10.1159/000151586

SchlüsselwörterHepatozelluläres Karzinom · Molekulare Pathogenese ·Zielgerichtete Therapie · Antiangiogenese · Tyrosinkinase-Inhibitoren · Monoklonale Antikörper

ZusammenfassungDas hepatozelluläre Karzinom (HCC) ist weltweit der fünft -häufigste Tumor, und aufgrund fehlender Therapieoptio-nen repräsentiert das HCC weltweit die dritthäufigsteKrebstodesursache. Die Inzidenz des HCC ist in Europaund Nordamerika kontinuierlich steigend, was durch dieAusbreitung von Hepatitis-C-Infektionen erklärt werdenkann. Die systemische Chemotherapie ist keine Optionfür die meisten HCC-Patienten, aber die zielgerichteteTherapie ist heute die hoffnungsvollste Strategie für diesystemische Behandlung des HCC. Eine erfolgreiche ziel-gerichtete Therapie muss Signaltransduktionswege hem-men, die auch im Spätstadium der Krebsentwicklung fürdas Tumorwachstum wichtig sind. Die p16/Rb- p53-,IGF2R-Kontrollpunke sowie onkogene Alterationen vonTelomerase, c-myc, Wnt/β-catenin, PI3K/Akt, Hedgehogund c-met/HGF sind am häufigsten involviert in die He-patokarzinogenese. Die attraktivste Strategie für die mo-lekulare Therapie scheint aber zurzeit die Hemmung vonVEGF (vascular endothelial growth factor) zu sein. Phase-I/II-Studien zeigten besonders lange progressionsfreieÜberlebenszeiten mit Antikörpern oder kleinen Molekü-len, die gegen den VEGF-Rezeptor-Signalweg gerichtetsind. Der Multikinase-Inhibitor Sorafenib, der eine starkeVEGF- und Raf-Hemmung vermittelt, konnte kürzlich ineiner Phase-III-Studie bei Patienten mit fortgeschrittenemHCC und guter Leberfunktion (Child A) das Überlebensignifikant verlängern. Seit diesem Jahr steht daher erst-malig eine effektive systemische Therapie für die Be-handlung von Patienten mit HCC zur Verfügung.

Key WordsHepatocellular carcinoma · Molecular pathogenesis ·Targeted therapy · Antiangiogenesis · Tyrosin kinase inhibitors · Monoclonal antibodies

SummaryHepatocellular carcinoma (HCC) constitutes the 5th mostfrequent cancer worldwide, and due to a lack of treat-ment options, HCC represents the 3rd most lethal cancerworldwide. The incidence of HCC is continuously risingin Europe and Northern America, which can be explainedby spreading of hepatitis C virus infections. Systemicchemotherapy is not an option for most patients withHCC. The most promising strategy for systemic treat-ment of HCC is targeted therapy. Successful targetedtherapy has to inhibit pathways which are necessary fortumor growth, even in the late stages of carcinogenesis.The p16/Rb, p53, and IGF2R checkpoints as well as onco-genic alterations of telomerase, c-myc, Wnt/β-catenin,PI3K/Akt, hedgehog, and c-met/HGF are most frequentlyinvolved in human hepatocarinogenesis. However, cur-rently, the most attractive target for molecular therapy ofHCC appears to be the vascular endothelial growth factor(VEGF). Phase I/II studies showed high progression-freesurvival rates with antibodies or small molecules target-ing the VEGF receptor pathway. Recently, a randomizedplacebo-controlled phase III study showed that the multi-kinase inhibitor sorafenib, which inhibits VEGF and Raf,significantly improves survival of patients with advancedHCC and Child A cirrhosis. As a consequence of thisstudy, sorafenib is now the first available drug for effec-tive systemic treatment of patients with advanced HCC.

Prof. Dr. Stefan KubickaAbteilung Gastroenterologie, Hepatologie und EndokrinologieMedizinische Hochschule HannoverCarl-Neuberg-Str. 1, 30625 Hannover, GermanyTel. +49 511 532-6766, Fax [email protected]

Molecular Pathogenesis and Targeted Therapy of Hepatocellular Carcinoma Lars Zender Stefan Kubicka

Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hanover, Germany

© 2008 S. Karger GmbH, Freiburg

Accessible online at: www.karger.com/onk

Fax +49 761 4 52 07 [email protected]

550_555_01008_kubicka:550_555_01008_kubicka 29.09.2008 13:01 Uhr Seite 550

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http://dx.doi.org/10.1159%2F000151586

cent cells at the stage of liver cirrhosis [5]. Telomere dysfunc-tion in turn induces chromosomal instability and initiation ofhepatocarcinogenesis. It has been shown that telomeres arecritically short in human HCC [6], and telomere shorteningcorrelates with increased aneuploidy in these tumors [7].Telomer dysfunction and heterogenous chromosomal translo-cations are difficult to target, but more than 90% of humanHCCs show activation of telomerase, which serves as a poten-tial molecular alteration for targeted therapy or virotherapy ofHCC [8, 9].Telomerase activity is transcriptionally controlled, and it hasbeen shown that the oncogene c-myc is an important transac-tivator for the hTert promotor [10]. Liver-specific expressionof c-myc reliably induces HCC in mice, and increased copynumbers of c-myc genes have been described in differentHCC mouse models and human HCCs [11]. At least in oneHCC mouse model, it has been shown that tumor growth de-pends on continuous activation of c-myc, indicating c-myc as amolecular target for HCC therapy [12]. In addition to c-myc,molecular alterations in human HCC are frequently observedin Wnt/β-catenin, PI3K/Akt, hedgehog, and the c-met/HGFoncogenic signaling pathway [13]. Abrogation of important cell cycle checkpoints is an earlyevent in hepatocarcinogenesis. The most commonly affectedcheckpoints in human hepatocarcinogenesis are p53/p14ARF,Rb/p16, and the IGF2R pathway. HCC-characteristic hotspotp53 mutations at codon 249 have been frequently observed inHCC of high incidence areas [13], whereas p53 gene alter-ations in European HCC are rare (approximately 10–30%)and occur generally not at the codon 249 [14]. In most HCCswith wildtype p53 expression, the p53 pathway is inhibited byother mechanisms such as deletions of p14ARF or overex-pression of MDM2 or gankyrin [11]. Neither Rb nor p16 areusually mutated in human HCC, but promoter hypermethyla-tion of p16 and overexpression of gankyrin account for sup-pression of the Rb/p16 pathway in the vast majority of humanHCCs [11]. In contrast to the Rb/p16 checkpoint, IGF2R isfrequently altered in human HCC by allelic loss (loss of het-erozygosity (LOH)). Since IGF2R impairs cell proliferationby promoting IGF2 degradation, IGF2 overexpression oftencooperates with LOH of the IGF2R locus in human HCC[11].It has been shown that HIF-1alpha, which plays a major rolein HIF-1 activation, is overexpressed in preneoplastic liver le-sions in mice and man [15]. HIF-1 is a transcription factor forvascular endothelial growth factor (VEGF), c-met, and in-sulin-like growth factor II (IGF-II). Elevated VEGF levels inserum and tissues have been known to be related to poorprognosis in patients with HCC, and recently it has beenshown that even some VEGF polymorphisms may be signifi-cant prognostic indicators for HCC patients [16]. Thus, thestrong hypervascular feature of HCC is at least partly mediat-ed by VEGF.

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Molecular Pathogenesis and Potential Targets for Molecular Therapy of Hepatocellular Carcinoma

A variety of hepatitis B virus (HBV) cellular interactions,which appear to have a role in the malignant transformationof hepatocytes, have been observed [1, 2]: i) cis-acting growthpromotion mechanisms resulting from HBV integration; ii)trans-acting growth promoting mechanisms involving HBVproducts (HBx, MHBst); iii) integration-provoked genetic in-stability indirectly leading to changes endowing growth advan-tage; iv) immune-mediated permanent cell death leading tocontinuous regeneration with a higher risk for mutations. A lot of evidence for an X gene-associated transformation hasbeen reported. For instance, transgenic mice containing aHBV enhancer X gene construct develop hepatocellular carci-noma (HCC), and transfected X gene is capable of transform-ing immortalized hepatocytes. X gene products are promiscu-ous transactivators of genes which contain AP-1, AP-2, orNFκB sites in their regulatory elements. It has been shownthat X protein transactivates the proto-oncogenes c-myc andc-fos which have important roles in hepatocarcinogenesis. Be-sides promiscuous gene transactivation, other X-mediatedmechanisms have been described which may also contributeto hepatocyte transformation (kinase activity, protease inhibi-tion, p53 inhibition). Furthermore, HBV codes for a set oftransactivating proteins outside the X gene sequences. Notwild type but C-terminal truncated preS2 polypeptides(MHBst) display an AP-1, AP-2, or NFκB site-dependenttransactivation function similar to the X protein.Hepatitis C virus (HCV) is a single-stranded RNA virus withno known DNA intermediate in its replication cycle. In addi-tion to transgenic HCV-HCC mouse models, it has beenshown by cell culture experiments that HCV may be directlyinvolved in hepatocarcinogenesis. The hepatitis C core proteinactivates the human proto-oncogene c-myc, and the nonstruc-tural protein NS3 is capable of transforming NIH3T3 cells.Targeting of viral proteins can be a successful strategy forvirus-induced cancers, as described in Epstein-Barr virus(EBV)-associated lymphomas [3]. However, growth of humanHCC is not dependent on single viral oncogenes, and the ma-jority of virus-associated HCCs do not even express any viralgene, indicating development by a hit-and-run mechanism.Thus, pharmacological or immunological targeting of viralgenes appears to not be a promising strategy for HCC therapy.It has been suggested that oncogene activation may occur notas an essential early step but as a redundant late event inhuman hepatocarcinogenesis, as a consequence of early chro-mosomal instability induced by telomere shortening in livercirrhosis. It has been shown that the frequency of replicationerrors in human HCC is low, but HCCs are associated with ahigh prevalence of chromosome copy number alterations andtranslocations [4]. During chronic liver disease, acceleratedtelomere shortening of hepatocytes occurs, resulting in senes-


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Current Advances in Targeted Therapy of HCCs

Phase I/II Studies with Epidermal Growth Factor InhibitorsSince there is evidence that the epidermal growth factor re-ceptor (EGFR) and its ligands (in particular TGF-α) are fre-quently involved in hepatocarcinogenesis, several phase IIstudies investigated the efficacy and toxicity of molecular ther-apies targeting the EGFR family. Small phase II studiesdemonstrated bad progression-free survival rates and no ac-tivity of the EGFR inhibitor gefitinib (Iressa®, AstraZeneca,Wedel, Germany) and the EGFR/Her2/neuR inhibitor lapa-tinib in HCC [17, 18]. In contrast, 2 other phase II studiesshowed low toxicity in the treatment of patients with liver cir-rhosis and HCC with the EGFR-tyrosin kinase inhibitor er-lotinib [19, 20]. In the study by Philip et al. [19] a high tumorcontrol rate of 59% and prolonged progression-free survivaldue to systemic therapy with erlotinib has been reported. Er-lotinib effects include antiangiogenic activity resulting fromdecreased VEGF levels [21], indicating that inhibition ofVEGF may be an important component of this anti-EGFRtherapy. Treatment of HCC with the EGFR antibody cetux-imab induced no remission and resulted in bad progression-free survival when cetuximab was applied as a single agent[22, 23], whereas a high remission rate of 24% and a satisfyingprogression-free survival (4.5 months) as well as overall sur-vival (OS) (9.2 months) have been reported in another phaseII study where cetuximab was given in combination with gem-citabine/oxaliplatin chemotherapy [24]. These results are

promising, but the contribution of cetuximab to this regimenremains to be defined.

Phase I/II Studies with the VEGF Antibody Bevacizumab The monoclonal VEGF antibody bevacizumab was investigat-ed in phase I/II studies in the treatment of HCC as a singleagent [25, 26], and in combination with chemotherapy [27, 28].Application of bevacizumab in these clinical trials significantlydecreased blood flow and vessel density of HCCs in magneticresonance and computer tomography imaging, confirming thestrong contribution of VEGF in the angiogenesis of thistumor. Treatment with bevacizumab was well tolerated in pa-tients with HCC, and resulted in long progression-free survival(table 1). Only in combination with gemcitabine/oxaliplatinchemotherapy, a high rate of bowel perforation (3%) has beenreported. Currently, the risk of bevacizumab treatment in pa-tients with portal hypertension and esophageal varices is un-known. To prevent possible bevacizumab-mediated varicealbleeding, Schwarz et al. [25] screened all patients for varices,and grade III/IV varices were ligated before entry into thestudy.

Clinical Studies with Multikinase InhibitorsThere are 2 phase I studies investigating pan-VEGF receptor(VEGFR) tyrosine kinase inhibitors in patients with HCC. Inthe study with AZD2171, a pan-VEGFR inhibitor with addi-tional activity against PDGR-α, PDGR-β, c-KIT, and FGFR1,the most frequent side effects were fatigue, hypertension, and

552 Onkologie 2008;31:550–555 Zender/Kubicka

Autor, year Protocol Patients, RR, PFS/ PFS at MSn % TTP 6 months, %

Anti-EGFRO’Dwyer et al., 2006 [17] gefitinib 31 3.2 2.3 NA NARamanathan et al., 2006 [18] lapatinib 37 5 2.3 NA 6.2Philip et al., 2005 [19] erlotinib 38 9 3.2 32 13Grünwald, 2007 [22] cetuximab 27 0 2.0 22.2 NALouafi et al., 2007 [24] GemOx + cetuximab 37 24 4.5 40 9.2

AntiangiogenesisKanai et al., 2006 [40] TSU-68 15 6 NA NA NASchwartz et al., 2006 [25] bevacizumab 30 10 6.5 NA NAMalka et al., 2007 [26] bevacizumab 24 12.5 3.5 17 NAZhu et al., 2006 [27] GemOx + bevacizumab 33 20 5.3 48 9.6Sun et al., 2007 [28] CapOx + bevacizumab 30 13.3 4.5 45 10.6

Multikinase-IAbou-Alfa et al., 2006 [31] sorafenib 137 5 5.6 37 9.5Llovet et al., 2007 [34] sorafenib 299a 2.3 5.5 NA 10.7Zhu et al., 2007 [32] sunitinib 26 3.8 4.1 35 11.6Faivre et al., 2007 [33] sunitinib 37 2.7 5.2 35 11.2

Multi-target approachThomas et al., 2007 [35] erlotinib + bevacizumab 29 20.6 8.8 NA 19

aPhase III study.RR = Response rate; PFS = progression-free survival; TTP = time to progression; MS = median survival; GemOx = gemcitabine/oxaliplatin; CapOx = capecitabine/oxaliplatin; NA = not applicable.

Table 1. Summaryof clinical studieswith targeted therapyin patients with hepa-tocellular carcinoma


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anorexia [29]. In a phase I trial with PTK787 which inhibits allknown VEGFR, platelet-derived growth factor receptor(PDGFR), and c-KIT, no remissions of HCC were observed,but 9 of 18 (50%) evaluable patients had stable disease [30].The predominant receptor tyrosine kinases that have beendemonstrated to be targeted by sunitinib are VEGF-2,PDGFR-α, PDGFR-β, c-KIT, FLT3, CSF-1, and RET, whilesorafenib strongly inhibits VEGF-2, VEGF-3, PDGFR-β, c-KIT, FLT3, and Raf-1. The IC50 values of sunitinib againstVEGFR-2, PDGFR-α, and PDGFR-β are lower compared tosorafenib, which may be relevant for the treatment of hyper-vascular tumors such as HCC. However, the Raf-1/MEK/ERKkinase pathway is frequently activated in solid tumors, and ef-fective targeting of Raf-1 by sorafenib may compensate forthe higher IC50 value in other receptor tyrosine kinases. Inclinical phase II studies, sunitinib and sorafenib showed simi-lar efficacy (table 1), but toxicity appears to be higher in HCCpatients treated with sunitinib [31–33]. The most frequentgrade 3/4 toxicities of sorafenib in the phase II study were fa-tigue (9.5%), diarrhea (8%), and hand-foot reaction (5.1%),while sunitinib toxicity in patients with HCC included throm-bocytopenia (43%), neutropenia (24%), central nervous sys-tem symptoms (24%), asthenia (22%), and hemorrhage(14%). In the European/Asian phase II study, dose reductionsof sunitinib were required in 27% of the patients. Whether thehigher toxicity of sunitinib compared to sorafenib may be ex-plained by a higher number of patients with impaired liverfunction and severe portal hypertension in the sunitinib study,remains unclear. An international placebo-controlled phase III study with firstline sorafenib treatment of patients with HCC was conducted[34]. 602 patients with advanced HCC (Barcelona Clinic LiverCancer (BCLC) stage B/C in the placebo group: 17/83%, andin the sorafenib group: 18/82%), but without limited liverfunction (Child-Pugh score A/B in the placebo group: 98/2%,and in the sorafenib group: 95/5%) were included in the study,and received either sorafenib 400 mg twice daily (n = 299) orplacebo (n = 303). Approximately 50% of the patients hadviral hepatitis, and 26% had alcohol-associated liver cirrhosis.The primary objectives of the study were OS and time tosymptomatic tumor progression which was assessed by theFSHI-8-TSP scoring system. Secondary endpoints were timeto tumor progression (TTP) and toxicity. Similar to the resultsfrom the phase II study, antitumoral activity based on RE-CIST criteria was disappointing, but TTP and OS were signifi-cantly prolonged by sorafenib treatment (table 2). Therapywith sorafenib was well tolerated and the most frequent toxic-ities were diarrhea (all grades/grade 3 in the sorafenib group:39/8%, and in the placebo group: 11/2%) and hand-food skinreaction (21/8% vs. 3/< 1%). Given the low toxicity and thesignificantly prolonged OS due to sorafenib therapy, it is inter-esting to note that the study did not reach the second primaryendpoint. Time to symptomatic tumor progression was not sig-nificantly different in both groups (hazard ratio 0.77), which

may be explained by the unsuitable scoring system for the de-termination of this endpoint. However, since cancer therapyshould not only prolong survival but also improve quality oflife of the patients, future clinical trials will have to show thatpatients with HCC will clinically benefit from systemic thera-py with sorafenib.

Combination of Targeted TherapiesThomas et al. [35] investigated the combination of bevacizum-ab and erlotinib in 29 patients with HCC in a phase II study,

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Table 2. Summary of the phase III study ‘sorafenib hepatocellular carci-noma assessment randomized protocol’ (SHARP)

Sorafenib Placebo Hazard(n = 299) (n = 303) ratio/p

Median age, years 65 66Gender, n

Male 87 87Female 13 13

Region, nEurope 88 87North America 9 10Other 3 3

Etiology, %Viral hepatitis (HCV/HBV) 29/19 27/18Alcohol 26 26Other 26 29

Child-Pugh score (A/B), % 95/5 98/2Prior therapies, %

Surgical resection 19 21Loco-regional therapies 39 41

BCLC stage, %B (intermediate) 18 17C (advanced) 82 83

ECOG, %0 54 541 38 392 8 7

Vascular invasion/extrahepatic spread, %present 70 70absent 30 30

ResponseComplete response 0 0Partial response, n (%) 7 (2.3) 2 (0.7)Stable disease, n (%) 211 (71) 204 (67)Progressive disease, n (%) 54 (18) 73 (24)Progression-free rate at 4 months, % 62 42Time to progression, weeks 24 12.3 0.58/0.000007Overall survival, weeks 46 34 0.69/0.00058Time to symptomatic progression 0.77 (n.s.)

HCV = Hepatitis C virus; HBV= hepatitis C virus; BCLC = BarcelonaClinic Liver Cancer; n.s. = not significant.


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and achieved a remarkable response rate of 20%, median pro-gression-free survival of 8.8 months, and OS of 19 months,which are the best results of all phase II studies with targetedtherapy (table 1). Because of these promising results, the com-bination of different targeted therapies has to be investigatesin further clinical studies in HCC patients.

Targeted Therapy in Multimodal Treatment StrategiesUntil now, there have been no data about the role of sorafenibor other targeted therapies in mutimodal treatment strategies[36]. Since objective response rates after targeted therapy ofHCC are negligible, neoadjuvant downstaging of advancedHCC by targeted therapy will not be promising. However,clinical trials in the near future will have to show if sorafenibwill improve survival after chemoembolization, percutaneoustumor ablation, surgical resection, or liver transplantation.

Searching for Reasonable Combinations of TargetedTherapies in the Future

To achieve a real breakthrough in targeted therapy of HCC,detailed knowledge of the molecular pathogenesis with identi-fication of key alterations is necessary. Recently, a series of pa-pers described the development of integrative oncogenomicapproaches based on mosaic cancer mouse models [37, 38].Spontaneously acquired genetic alterations in mouse tumorsof defined genetic origin are used to select lesions from com-plex human cancer genomes, which are necessary in the con-text of distinct oncogenic networks. The great advantage ofthis approach is that pinpointed candidate genes can be rapid-ly functionally validated in the right genetic context in vivo,which significantly increases confidence for later therapeuticdevelopments [39]. Hopefully, with the help from suitablemouse models, comparative oncogenomis and target evalua-tion we will be able to identify the key targets in differentoncogenic networks, which would enable us to establish an ef-fective individualized targeted cancer therapy in the future.

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Molecular Pathogenesis and Targeted Therapy of Hepatocellular Carcinoma