Targeted therapy of hepatocellular cancer

1. Introduction

2. Development of HCC

3. Receptors and signaling

pathways in HCC: molecular

targets

4. Angiogenesis in HCC:

molecular targets

5. Expert opinion

Review

Targeted therapy ofhepatocellular cancerPiotr Jan WysockiUniversity of Medical Sciences, Department of Chemotherapy, Greater Poland Cancer Center,

ul. Garbary 15, Poznan 61-866, Poland

Importance of the field: Hepatocellular cancer (HCC) is the fifth most common

malignancy worldwide and third leading cause of cancer death. HCC is highly

resistant to conventional systemic therapies, and prognosis for advanced HCC

patients remains poor. However, identification of signaling pathways respon-

sible for HCC growth and progression such as RAS/RAF/MEK/ERK or PI3K/AKT/

mTOR has determined crucial molecular targets and led to development of

novel promising targeted therapies.

Areas covered in this review: This article presents molecular mechanisms

responsible for development and progression of HCC and strategies aimed

to block important molecules involved in signal transduction. It also reviews

the clinical studies evaluating efficacy and safety of novel targeted

approaches for treatment of this malignancy.

What the reader will gain: Inhibition of molecular targets (ligands, membrane

receptors and receptor-associated kinases) represents a promising strategy for

treatment of HCC; in the case of sorafenib, this has already been demon-

strated to significantly improve survival of advanced HCC patients. This article

reviews novel therapeutic approaches that are based on combinations of

different targeted agents with or without classic cytotoxic drugs.

Take home message: Despite significant progress, advanced HCC remains an

incurable disease, and the overall efficacy of recently approved targeted

therapy (sorafenib) remains moderate. It is to be hoped that several ongoing

clinical trials evaluating novel targeted approaches for treatment of HCC will

lead to further improvement in the management of advanced disease.

Keywords: angiogenesis, hepatocellular cancer, mTOR inhibitors,

receptor tyrosine kinase inhibitors, signaling pathways, targeted therapy

Expert Opin. Investig. Drugs (2010) 19(2):265-274

1. Introduction

Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide andthird leading cause of cancer death. In 2000, HCC accounted for 7.5% of cancer inmen and 3.5% in women. There are some certain geographic regions in Asia andAfrica where the incidence of HCC is 40 times higher than in other regions of theworld due to endemic hepatitis B virus (HBV) infection [1-3]. The incidence of HCCis rising globally; however, a much sharper increase has been documented inWesterncountries, mainly because of the high prevalence of hepatitis C virus (HCV)infection [4]. In Western countries, 30 – 40% of HCC cases are diagnosed at anearly stage that is amenable to potentially curative treatments such as surgery(resection or liver transplantation) and locoregional procedures (radiofrequencyablation). Up to 70% of patients diagnosed with early HCC can survive 5 years.However, locally advanced or relapsing (after locoregional treatment) disease has apoor prognosis due to underlying liver disease and lack of effective systemictreatment. Conventional chemotherapy has not been demonstrated to prolongsurvival of patients with locally advanced or metastatic HCC. However, recent

10.1517/13543780903514110 © 2010 Informa UK Ltd ISSN 1354-3784 265All rights reserved: reproduction in whole or in part not permitted

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advances in our understanding of HCC biology and biotech-nology have led to the development of novel molecularlytargeted agents for this malignancy. The aim of this article is toreview the molecular mechanisms responsible for developmentand progression of HCC, and the role of targeted therapies inthe treatment of HCC.

2. Development of HCC

Hepatocarcinogenesis is a multistep process initiated by exter-nal stimuli that lead to genetic changes in hepatocytes or stemcells, resulting in proliferation, apoptosis, dysplasia and neo-plasia [5-7]. Risk factors for HCC development include viralinfections (HBV or HCV), exposure to aflatoxin B, chronicalcohol intake, and cirrhosis. Almost 80% of HCC casesdevelop in cirrhotic liver [5,6]. The majority of HCC casesare related to chronic viral infections. However, the mechan-isms by which HBV or HCV induce malignant transforma-tion seem to be different. HBV is a DNA virus; its DNAintegrates into the host genome, inducing chromosome insta-bility [8,9] and insertional mutations that may activate variousoncogenes such as cyclin A [10,11]. Replication of HBV requiresexpression of several viral proteins, in particular X protein(HBx) [12]. HBx acting as a transactivator upregulates severaloncogenes such as c-myc and c-jun [13,14] and transcriptionalfactors like NF-kB or AP-2 [15,16]. Additionally, HBx activatespromoters of genes encoding IL-8, TNF, TGF-ß andEGFR [17]. HBx that is localized in cytoplasm can stimulateseveral signal transduction pathways: JAK/STAT [18], RAS/RAF/MAPK [19], and Wnt/ß-catenin [20]. Furthermore, HBxmay impair various functions of p53 protein [21] and stimulateproduction of angiogenic factors such as VEGF by HCCcells [22]. Since HCV genome (RNA) does not integrate intothe host genome, the major role in hepatocarcinogenesis issupposed to be played by HCV viral proteins – core, NS3 andNS5A. HCV core protein can promote apoptosis or cellproliferation through interaction with p53 [23] or via upregu-lation of Wnt-1 at the transcriptional level [24]. NS4Aand NS4B proteins mediate translational inhibition anddegradation of various cellular proteins [25].Aflatoxin B, a fungal toxin present in contaminated ground-

nuts, is a very potent mutagen that reacts with guanine inDNA, leading to mutations. Endemic exposure to aflatoxin B

is common in some Asian and African countries and isassociated with a high frequency of HCC-carrying mutationsin p53 at codon 249 [26].

Cirrhosis is present in about 80 – 90% of HCC patientsand constitutes the largest single risk factor. The risk ofdeveloping HCC in cirrhotic liver varies with the underlyingdisease. The highest estimated 5-year cumulative risk isobserved in HCV cirrhosis (17 – 30%), followed by hemo-chromatosis (21%), HBV cirrhosis (10 – 15%), alcoholiccirrhosis (8%), and biliary cirrhosis (4%) [4]. In cirrhotic liver,changes in fat metabolism associated with activation of adi-pocyte-like pathways are supposed to be involved in neoplastictransformation [27,28]. Additionally, steatosis, steatohepatitisand associated oxidative stress are recognized as importantcofactors in HCC development [29].

3. Receptors and signaling pathways in HCC:molecular targets

3.1 EGFREGFR is expressed on the surface of hepatocytes and plays arole in regeneration after liver injury or partial hepatec-tomy [30]. Hepatocarcinogenesis and proliferation of HCCcells depends on stimulation of EGFR by its ligands, TGF-aor EGF [31-33]. Activation of EGFR initiates two signalingpathways, RAS/RAF/MEK/ERK and PI3K/AKT/mTOR,which play a major role in the biology of HCC [7].Thereare two strategies for targeting EGFR: neutralizing monoclo-nal antibodies (cetuximab or panitumumab), and tyrosinekinase inhibitors (TKIs; erlotinib, gefitinib and lapatinib,which also inhibits the HER2 receptor). Monoclonal anti-bodies bind to the extracellular domain of EGFR and blockthe ligand-induced receptor activation; receptor TKIs blockkinase-dependent downstream signaling. Both approachesdemonstrated significant inhibitory activity in vitro againstHCC cell cultures [34,35].

The clinical efficacy of erlotinib in HCC patients has beenevaluated in two Phase II clinical studies. In a study by Philipand colleagues, 38 patients with unresectable or metastaticHCC were receiving 150 mg of erlotinib daily [36]. Expressionof EGFR was detected in 88% of the patients. Objectiveclinical responses were observed in three patients. At 6 monthsof treatment, 32% of patients remained progression-free, andmedian OS (overall survival) was 13 months. In analogicalstudy involving 40 patients, no objective clinical responseswere observed [37]. At 4 months of treatment, 43% of patientsremained progression-free and the median OS was10.75 months. Lapatinib was evaluated in a cohort of40 patients with advanced HCC in a Phase II study. Theobjective response rate was 5%. Median progression-freesurvival (PFS) and OS were 2.3 and 6.2 months, respec-tively [38]. In a similar study in a group of 31 patients, gefitinibinduced 3% of objective responses and 22.6% of SD (stabledisease). Median PFS and OS were 2.8 and 6.8 months,respectively [39].

Article highlights.

. Molecular mechanisms of hepatocellular cancer (HCC)development and progression.

. Receptors and signal transduction molecules astherapeutic targets.

. Molecular targets in HCC-associated angiogenesis.

. Safety and efficacy of novel targeted therapies fortreatment of HCC.

. Promising future strategies for treatment of HCC.

This box summarises key points contained in the article.

Targeted therapy of hepatocellular cancer

266 Expert Opin. Investig. Drugs (2010) 19(2)

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In a Phase II study, 30 patients with advanced or metastaticHCC received cetuximab. No clinical responses were seen,and disease stabilization was observed in 17% of patients.Median PFS and OS were 1.4 and 9.6 months, respec-tively [40]. In a similar study, 27 advanced HCC patientswere administered cetuximab. The disease stabilization ratewas 44.4% (no objective responses) and median PFS,1.8 months [41]. The clinical efficacy of cetuximab combinedwith standard chemotherapy was analyzed in a multicenterPhase II study that included 43 treatment-naive advancedHCC patients. Patients were treated with cetuximab (standardregimen) and chemotherapy, repeated every 2 weeks(gemcitabine + oxaliplatin). The objective response rate was23% and disease stabilization was observed in 65% of patients.Median PFS and OS were not reported [42].

3.2 IGF-R1Aberrant activation of insulin-like growth factor signalingpathway resulting from upregulation and activation ofIGF-1R can be detected in 20% of HCC. Additionally,IGF-II expression is increased in 12 – 44% of HCC sam-ples [43]. In a xenograft HCC model, monoclonal antibodytargeting IGF-1R delayed tumor growth and improvedsurvival of treated animal [44]. In a Phase I clinical study,one patient with heavily pretreated HCC experienced SD of> 9 months following administration of IMC-A12 mono-clonal antibody [45]. A Phase II study evaluating IMC-A12in patients with advanced HCC has been recently initiated.

3.3 PI3K/AKT/mTOR pathwayThe phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pro-tein cascade is a major signaling pathway associated withreceptor tyrosine kinases (RTKs) that have been identifiedin cancer cells [46]. The second important pathway in HCC isthe RAS/RAF/MAPK cascade [47]. Various RTKs that may beexpressed by cancers cells (e.g., VEGFR-1 [48], PDGFR-a [49],EGFR [50], or c-MET [51]) use the PI3K/Akt/mTOR signalingpathway to shape the phenotype and function of malignantcells. Activation of RTKs leads to activation of PI3K, whichcan be also activated indirectly via RAS. The function of PI3Kis negatively controlled by a phosphatase and tensinhomologue (PTEN). Loss of functional PTEN is frequent(> 55%) in HCC [52]. However, the frequency of PTENmutations is much lower than in other malignancies(range, 0 – 11%) [53]. Activated PI3K upregulates expressionof NF-kB-dependent survival genes such as Bcl-XL [54].PI3K, via a 3-phosphoinositide-dependent protein kinase 1(PDK-1), activates AKT [55]. AKT is a serine/threonine kinasethat phosphorylates and inactivates several pro-apoptoticproteins such as Bad and caspase-9.

One important downstream effector of AKT is mTOR(mammalian target of rapamycin). Activation of the PI3K/AKT/mTOR pathway correlates with poor prognosis inHCC [56]. Phosphorylation of mTOR and its downstreamtarget, S6K1, were detected in 15 and 45% of human HCC

cases, respectively [57]. Through its downstream effectors,activated mTOR regulates numerous cellular processes suchas initiation of mRNA transcription and protein translation.mTOR regulates essential signal transduction pathways and isinvolved in coupling growth stimuli to cell cycle progres-sion [58]. Phosphorylation of mTOR leads to upregulationof hypoxia-inducible factors alpha (HIF-1a and HIF-2a).Transcriptional targets of HIFs are strongly associatedwith metastasis.

The CXCR4, a chemokine receptor that is supposed to beone of the major metastatic mediators, was shown to beupregulated by HIF in HCC [59,60]. Similarly, hypoxiaincreases expression of MMP2 and MMP9 [61]; and HIFupregulates lysyl oxidase, which facilitates metastasis throughalteration of extracellular matrix components such as elastinand collagen [62]. One of the targets of HIF-2a is Oct4, a geneencoding a POU-domain transcription factor that is a keyregulator of stem-cell behavior. It is possible that Oct4 mod-ulates tumor biology through promotion of the growth of‘cancer stem cells’, which seem to be pivotal for maintainingtumor self-renewal and chemotherapy resistance [63]. HIFs areassociated with malignant phenotype of cancer cells, not onlyregulating tumor cell phenotype but also inducing angiogen-esis through expression of VEGF or PDGF [64]. The HIFs arealso responsible for tumor chemoresistance. Platelet-derivedgrowth factor B (PDGF-B) not only stabilizes novel vesselsbut also decreases penetration of anticancer drugs throughincreasing of interstitial hypertension [65]. Another mechanismof chemoresistance mediated by HIFs is upregulation ofMDR1 [66].

The PI3K/AKT/mTOR pathway may be inhibited atvarious levels. PI3K inhibitors such as wortmannin andLY294002 have demonstrated some efficacy in animalHCC models [67]. Another inhibitor, FTY720, was shownto induce apoptosis in HCC cell lines, as well as inhibitinggrowth of HCC xenografts [68]. Activation of AKT can beinhibited by an orally bioavailable alkylphospholipid, perifo-sine, which has been already tested in a few Phase I stud-ies [69,70]. HIFs represent another interesting therapeutictarget. In a murine model, administration of HIF-1aantisense into HCC cells decreased intracellular levels ofHIF-1a and VEGF and increased therapeutic efficacy ofdoxorubicin [71].

However, the most promising target in the PI3K/AKT/mTOR pathway is represented by mTOR. Inhibitors ofmTOR are currently used as immunosuppressant drugs fol-lowing liver transplantation. The effectiveness of mTORblockade with rapamycin analogues has been tested in pre-clinical HCC models [53]. Rapamycin was shown to inhibitproliferation of HCC cell line in vitro and growth of HCCtumors in animal models [72]. Everolimus (RAD001) effec-tively inhibited growth of HCC in vitro and in vivo, andsignificantly enhanced cytotoxic effect of cisplatin in HCCcell lines [73,74]. Another mTOR inhibitor, sirolimus, wasevaluated in 21 advanced HCC patients [75]. One patient

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experienced partial response, and five remained progression-free at 3 months. Median OS was 6.5 months. A Phase I/IIstudy evaluating the clinical efficacy of the mTOR inhibitoreverolimus (RAD001) in advanced HCC has beenrecently initiated.

3.4 RAS/RAF/MAPK pathwayBeside the PI3K/AKT/mTOR pathway, the MAPK pathwayplays a major role in hepatocarcinogenesis. The MAPKpathway includes a cascade of phosphorylation involvingkinases such as RAS, RAF, mitogen-activated protein extra-cellular kinase (MEK) and extracellular signal-regulated kinase(ERK). The MAPK pathway can be activated by RTKs such asEGFR, HER2, IGF-R1 or c-MET by integrin receptors or bysignaling from ion channels [76]. Activation of the MAPKpathway induces cell proliferation, migration and inhibitionof apoptosis [77]. This pathway is often aberrantly activated inHCC [78,79], and there are several molecular mechanismsresponsible for its activation. HCV core protein can directlyactivate the Raf/MEK/ERK cascade [80]. Loss of RAF kinaseinhibitor protein was demonstrated to stimulate HCC pro-liferation and migration [81]. Overexpression of RAS was alsoobserved in HCC tumors [82]. As in the case of the PI3K/AKT/mTOR pathway, the RAS/RAF/MEK/ERK pathway may beinhibited at various levels. In order to be capable of signaltransduction, RAS must undergo post-translational modifica-tion by incorporation of prenyl moieties (farnesyl andgeranylgeranyl groups).Inhibitors of farnesyl transferase prevent prenylation of

RAS proteins; to date, several inhibitors have been devel-oped. Among them, ABT-100 was shown to prevent thedevelopment of chemically induced HCC in rats [83]. Inhi-bition of MEK was also shown to prevent development ofHCC and increase apoptosis in existing HCC tumors inmice [84]. In another study, administration of MEK inhib-itor resulted in dose-dependent growth inhibition of HCCxenografts [85].Targeting RAF kinase is currently the most promising

targeted approach for treatment of HCC. Sorafenib, amulti-TKI, has demonstrated significant clinical efficacy ina pivotal Phase III trial (SHARP), which led to its approval forHCC treatment by international regulatory agencies [86].Sorafenib tosylate is a bisaryl urea first designed as anin vitro inhibitor of the RAF-1 protein. However, sorafenibwas also shown to inhibit the tyrosine kinases of VEGFR-1,VEGFR-2, VEGFR-3, PDGFR-B, FLT-3 and c-KIT. In thepivotal Phase III study, 602 treatment-naive, advanced HCCpatients were randomly assigned to receive sorafenib 400 mgb.i.d. or placebo [86]. Patients recruited in the study hadnormal liver function (Child–Pugh class A). Sorafenib signif-icantly improved median PFS and OS compared with placebo(5.5 vs 2.8 and 10.7 vs 7.9 months, respectively). The hazardratio (HR) for death in the sorafenib group was significantlyreduced, to 0.69 (95% CI, 0.55 – 0.87; p < 0.001). Theresponse rate was similarly low in both arms: 2% PR (partial

response) and 71% SD in the sorafenib arm and 1% PR and67% SD in the placebo arm. Disease control was significantlyhigher in the sorafenib group (43 vs 32%; p = 0.002). Toxicityof the treatment was acceptable, with diarrhea, weight loss,hand–foot skin reaction and hypophosphatemia being themost frequently reported adverse events.

The efficacy of sorafenib in patients with advanced HCCwas confirmed in another Phase III trial, which involved207 patients from the Asia-Pacific region [87]. Sorafenibsignificantly prolonged median OS compared with placebo(6.5 vs 4.2 months, respectively). The reduction of HR forsurvival in the sorafenib arm (0.68; 95% CI, 0.50 – 0.93;p = 0.014) was comparable to the SHARP trial. Based on thePhase III studies, sorafenib is now approved for the treatmentof patients with advanced HCC with adequate liver function(Child–Pugh class A).

4. Angiogenesis in HCC: molecular targets

As in other human cancers, angiogenesis is pivotal for thedevelopment and progression of HCC. Several studies dem-onstrated that the intensity of angiogenesis in HCC (assessed bymicrovessel density) correlated with the risk of vascular inva-sion, metastasis and patient prognosis [88,89]. VEGF (mainly itsA-isoform, VEGF-A) is one of the most potent angiogenicfactors. The effect of VEGF-A is mediated via two receptors:VEGFR-1 (Flt-1) and VEGFR-2 (KDR). VEGFR-2 mediatesall of the known cellular responses to VEGF, and VEGFR-1 issupposed to modulate VEGFR-2 signaling. In HCC xeno-grafts, tumor growth was demonstrated to be tightly controlledby the level of VEGF expression [90]. The expression of VEGFincreases in parallel to HCC development [91]. A quantitativeanalysis revealed that VEGF was expressed in 64% of encap-sulated HCC and in 78% of non-encapsulated (more aggres-sive) HCC [92]. In another study, expression of VEGF wasdetected in 89% of HCC samples [93].

Expression of VEGF and other angiogenic factors such asbFGF or angiopoietin 2 correlates with vascular density,invasion and metastasis in HCC [94,95]. Moreover, HCCcell lines were demonstrated to express VEGF receptors, whichmay be responsible for VEGF-mediated autocrine stimulationof tumor growth [96]. The VEGF pathway may be targeted bytwo approaches, using either anti-VEGFmonoclonal antibodyor inhibitors of the receptor tyrosine kinase associatedwith VEGFR.

4.1 Targeting VEGFBevacizumab is a humanized monoclonal antibody that neu-tralizes all isoforms of VEGF. This drug is currently approvedby the FDA for treatment of colon, breast and non-small celllung cancers, in combination with chemotherapy. In a HCCxenograft model, bevacizumab significantly decreased vesseldensity and prolonged time to progression of tumor-bearingmice [97]. In a Phase II clinical trial, 46 patients with locallyadvanced HCC were treated with bevacizumab 5 or 10 mg/kg



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i.v. every 2 weeks [98]. Objective clinical responses wereobserved in 13%, and disease stabilization lasting ‡ 6 monthsin 65% of patients. Median PFS was 6.9 months. OS was 53%at 1 year, 28% at 2 years, and 23% at 3 years. In anotherPhase II study, among 38 evaluable patients bevacizumabinduced 16% PR and 47% SD [99].

Treatment based on bevacizumab combined with erlotinibwas evaluated in 40 patients in another Phase II trial. Thepartial response rate was 25%. Median PFS was9 months; OS, 15.65 months. This combination will befurther evaluated in a Phase III clinical study [100].

A few clinical trials have evaluated various combinations ofbevacizumab with chemotherapy. The efficacy of bevacizumabwith gemcitabine and oxaliplatin in advanced HCC wasevaluated in a Phase II trial [101]. In a group of 30 evaluablepatients, the objective response rate (ORR) was 20%; SD,27%. Median OS and PFS were 9.6 and 5.3 months, respec-tively. Other first-line therapy based on bevacizumab com-bined with capecitabine and oxaliplatin was evaluated in30 patients with advanced HCC [102]. In this trial, 11% ofpatients achieved partial response and 78% disease stabiliza-tion. Median PFS was 5.4 months. Bevacizumab combinedwith capecitabine was evaluated in another Phase II study.Among 45 patients with advanced or metastatic HCC, theobjective response rate (CR + PR) was 16% and SD wasobserved in 44%. Median OS and PFS were 4.1 and10.7 months, respectively [103].

4.2 Targeting VEGF receptorsElucidation of the important role of receptor tyrosine kinasesin angiogenesis has identified novel promising therapeutictargets. The introduction of TKIs such as sunitinib or sor-afenib represents a major breakthrough in the treatment ofrenal cell cancer [104]. In HCC, the first approved multi-kinaseinhibitor, sorafenib, exerts its effect not only againsttumor cells by targeting RAF kinase, but also againstendothelial cells and pericytes by targeting VEGFR-1,VEGFR-2, VEGFR-3 and PDGFR-b, which blocks VEGFand PDGF-dependent angiogenesis.

Sunitinib malate is another orally available multi-kinaseinhibitor that targets receptor tyrosine kinases of VEGFR-1,VEGFR-2, VEGFR-3, PDGFR-a, PDGFR-b, FMS-liketyrosine kinase 3 (FLT-3) and c-KIT. In an European studythat included 45 patients with unresectable HCC, adminis-tration of sunitinib induced 2% objective responses (1 CR)and 40% SD [105]. The median OS was 9.3 months; PFS,2.8 months. In another study conducted in the United States,treatment with sunitinib in 34 patients resulted in 2.9% PRand 50% SD. The median OS and PFS were 9.8 and3.9 months, respectively [106].

Brivanib alaninate is an oral, dual inhibitor of VEGFR andFGFR tyrosine kinases. In a Phase II clinical trial, HCCpatients – either treatment-naive or previously treated withantiangiogenic inhibitor (sorafenib or thalidomide) – receivedbrivanib. Brivanib demonstrated some clinical efficacy in

first- and second-line therapy. The median OS oftreatment-naive patients was 10.0 months [107].

Currently, sunitinib and brivanib are being tested inPhase III studies, and other antiangiogenic multi-kinase inhi-bitors such as pazopanib, vandetanib, or cediranib are beingevaluated in early-phase clinical trials.

5. Expert opinion

Significant progress in cancer molecular biology and biotech-nology resulted in the development of various targetedapproaches for the treatment of HCC (Table 1). Clinical trialsevaluating the efficacy of sorafenib demonstrated that targetedtherapy can significantly improve clinical outcome and pro-long survival of patients with advanced HCC. However, theera of targeted therapies for HCC is just beginning, and manynew drugs are expected to emerge. The cytostatic mechanismof action of targeted agents is reflected by their ability toinduce prolonged disease stabilization rather than cure. There-fore, the development of therapeutic approaches based onmolecularly targeted drugs must take into account that theseagents must have low toxicity to be suitable for the chronictreatment of a malignant disease.

There are still many unanswered questions associated withtargeted approaches in the treatment of HCC. Novel drugsrequire novel biomarkers. Despite the obvious clinical efficacyof sorafenib, many patients turn out to be refractory to thistherapy. Individualization of targeted therapies depends onbiomarkers, which help to predict response to treatment. Inthe case of sorafenib, phosphorylated ERK seems to representsuch a promising biomarker. A Phase II trial evaluating theefficacy of sorafenib revealed that increased levels of phospho-ERK (a downstream target of RAF) in HCC samples pre-dicted a significantly prolonged PFS compared with patientswith low levels of phospho-ERK [108]. In the case of othertargeted drugs currently used for treatment of various malig-nancies (such as bevacizumab, sunitinib or temsirolimus),validated biomarkers are still missing.

The efficacy of sorafenib was demonstrated mostly inpatients with Child–Pugh class A liver function, due toparticular clinical trial inclusion criteria. However, patientswith good liver condition represent only a minority of HCCpatients. Therefore, prospective evaluation of sorafenib inpatients with liver function worse than Child–Pugh class Ais crucial. A recent, retrospective subgroup analysis of theSHARP study (presented at the 44th Annual Meeting of theEuropean Association for the Study of the Liver [EASL])revealed that sorafenib was similarly effective in patients withintermediate and late-stage liver cancer (Barcelona ClinicLiver Cancer stages B and C).

Another aspect that remains to be determined is the efficacyof targeted therapies in the adjuvant setting. Since regrowth ofHCC tumors following surgery or transarterial chemoembo-lization is associated with rapid angiogenesis, antiangiogenicstrategies may prove effective in reducing the relapse rate. The

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rationale for combining local modalities (transcatheterarterial embolization or chemoembolization) with systemictargeted therapies has been recently extensively reviewedby Strebel and Dufour [109]. Studies seeking to determinethe molecular pathways responsible for HCC developmentand progression indicate the existence of crosstalk betweenvarious levels of different signal-transducing cascades.This knowledge is expected to help identify novel mechanismsof resistance to targeted agents and determine moleculartargets in complementary pathways, which must beblocked simultaneously.Sorafenib is the first systemic therapy to demonstrate a

survival benefit for unresectable HCC. To date, sorafenibremains the only approved targeted agent in systemictreatment of HCC; however, it is access to this drug that

remains a major concern. Currently, only the richest countriescan afford to provide novel, approved therapies to all cancerpatients. Unfortunately, the highest incidence of HCC isobserved in poor countries, owing to endemic HBV infection.Therefore, the wide use of novel targeted therapies requirescompromise between governments, healthcare systems andpharmaceutical companies. One has to hope that such acompromise, which may dramatically improve the prog-nosis for HCC patients worldwide, will not remain anunfulfilled dream.

Declaration of interest

The author states no conflict of interest and has received nopayment in preparation of this manuscript.

Table 1. Clinical trials evaluating targeted therapies in HCC treatment.

Treatment Phase No. of patients CR ++ PR (%) SD (%) PFS [months] OS [months] Ref.

Monotherapy

Sorafenib vs placebo III 602 2.3 43 vs 32 5.5 vs 2.8 10.7 vs 7.9 [86]

Sorafenib vs placebo III 271 3.3 vs 1.3 54 vs 27.6 2.8 vs 1.4 6.5 vs 4.2 [87]

Erlotinib II 38 9 50 3.0 13 [36]

Erlotinib II 40 0 42.5 ND 10.75 [37]

Lapatinib II 57 5 26 2.3 6.2 [38]

Gefitinib II 31 3 22.6 2.8 6.5 [39]

Cetuximab II 30 0 17 1.4 9.6 [40]

Cetuximab II 32 0 44.4 1.8 ND [41]

Bevacizumab II 46 13 54 6.9 12.4 [98]

Bevacizumab II 43 16 47 ND ND [99]

Bevacizumab + erlotinib II 40 25 42.5 9.0 15.65 [100]

Sunitinib II 45 2 40 2.8 9.3 [105]

Sunitinib II 34 2.9 50 3.9 9.8 [106]

Combined treatment

Bevacizumab + GEMOX II 33 20 27 5.3 9.6 [101]

Bevacizumab + CAPOX II 30 11 78 5.4 ND [102]

Cetuximab + GEMOX II 43 23 65 ND ND [42]

CAPOX: Capecitabine + oxaliplatin; CR: Complete response; GEMOX: Gemcitabine + oxaliplatin; ND: No data; OS: Overall survival; PFS: Progression-free survival;

PR: Partial response.



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Bibliography1. Bosch FX, Ribes J, Diaz M, Cleries R.

Primary liver cancer: worldwide incidence

and trends. Gastroenterology

2004;127(5 Suppl 1):S5-16

2. Parkin DM, Bray F, Ferlay J, Pisani P.

Estimating the world cancer burden:

Globocan 2000. Int J Cancer

2001;94(2):153-6

3. Pisani P, Bray F, Parkin DM. Estimates of

the world-wide prevalence of cancer for 25

sites in the adult population. Int J Cancer

2002;97(1):72-81

4. Fattovich G, Stroffolini T, Zagni I,

Donato F. Hepatocellular carcinoma in

cirrhosis: incidence and risk factors.

Gastroenterology

2004;127(5 Suppl 1):S35-50

5. Farazi PA, DePinho RA. Hepatocellular

carcinoma pathogenesis: from genes to

environment. Nat Rev Cancer

2006;6(9):674-87

6. Thorgeirsson SS, Grisham JW. Molecular

pathogenesis of human hepatocellular

carcinoma. Nat Genet 2002;31(4):339-46

7. Villanueva A, Newell P, Chiang DY, et al.

Genomics and signaling pathways in

hepatocellular carcinoma. Semin Liver Dis

2007;27(1):55-76

8. Brechot C, Pourcel C, Louise A, et al.

Presence of integrated hepatitis B virus

DNA sequences in cellular DNA of human

hepatocellular carcinoma. Nature

1980;286(5772):533-5

9. Murakami Y, Saigo K, Takashima H, et al.

Large scaled analysis of hepatitis B virus

(HBV) DNA integration in HBV related

hepatocellular carcinomas. Gut

2005;54(8):1162-8

10. Minami M, Daimon Y, Mori K, et al.

Hepatitis B virus-related insertional

mutagenesis in chronic hepatitis B patients

as an early drastic genetic change leading to

hepatocarcinogenesis. Oncogene

2005;24(27):4340-8

11. Wang J, Chenivesse X, Henglein B,

Brechot C. Hepatitis B virus integration in

a cyclin A gene in a hepatocellular

carcinoma. Nature 1990;343(6258):555-7

12. Feitelson MA, Duan LX. Hepatitis B

virus X antigen in the pathogenesis of

chronic infections and the development of

hepatocellular carcinoma. Am J Pathol

1997;150(4):1141-57

13. Balsano C, Avantaggiati ML, Natoli G,

et al. Full-length and truncated versions of

the hepatitis B virus (HBV) X protein (pX)

transactivate the cmyc protooncogene at

the transcriptional level. Biochem Biophys

Res Commun 1991;176(3):985-92

14. Twu JS, Lai MY, Chen DS, Robinson WS.

Activation of protooncogene c-jun by

the X protein of hepatitis B virus. Virology

1993;192(1):346-50

15. Chirillo P, Falco M, Puri PL, et al.

Hepatitis B virus pX activates NF-kappa

B-dependent transcription through a

Raf-independent pathway. J Virol

1996;70(1):641-6

16. Seto E, Mitchell PJ, Yen TS.

Transactivation by the hepatitis B virus X

protein depends on AP-2 and other

transcription factors. Nature

1990;344(6261):72-4

17. Andrisani OM, Barnabas S. The

transcriptional function of the hepatitis B

virus X protein and its role in

hepatocarcinogenesis (Review). Int J Oncol

1999;15(2):373-9

18. Lee YH, Yun Y. HBx protein of hepatitis B

virus activates Jak1-STAT signaling.

J Biol Chem 1998;273(39):25510-5

19. Benn J, Schneider RJ. Hepatitis B virus

HBx protein activates Ras-GTP complex

formation and establishes a Ras, Raf, MAP

kinase signaling cascade. Proc Natl Acad

Sci USA 1994;91(22):10350-4

20. Cha MY, Kim CM, Park YM, Ryu WS.

Hepatitis B virus X protein is essential for

the activation of Wnt/beta-catenin

signaling in hepatoma cells. Hepatology

2004;39(6):1683-93

21. Ueda H, Ullrich SJ, Gangemi JD, et al.

Functional inactivation but not structural

mutation of p53 causes liver cancer.

Nat Genet 1995;9(1):41-7

22. Lee SW, Lee YM, Bae SK, et al. Human

hepatitis B virus X protein is a possible

mediator of hypoxia-induced angiogenesis

in hepatocarcinogenesis. Biochem Biophys

Res Commun 2000;268(2):456-61

23. Yamanaka T, Kodama T, Doi T.

Subcellular localization of HCV core

protein regulates its ability for p53

activation and p21 suppression.

Biochem Biophys Res Commun

2002;294(3):528-34

24. Fukutomi T, Zhou Y, Kawai S, et al.

Hepatitis C virus core protein stimulates

hepatocyte growth: correlation with

upregulation of wnt-1 expression.

Hepatology 2005;41(5):1096-105

25. Florese RH, Nagano-Fujii M, Iwanaga Y,

et al. Inhibition of protein synthesis by the

nonstructural proteins NS4A and NS4B of

hepatitis C virus. Virus Res

2002;90(1-2):119-31

26. Ozturk M. p53 mutation in hepatocellular

carcinoma after aflatoxin exposure. Lancet

1991;338(8779):1356-9

27. Terasaki S, Kaneko S, Kobayashi K, et al.

Histological features predicting malignant

transformation of nonmalignant

hepatocellular nodules: a prospective

study. Gastroenterology

1998;115(5):1216-22

28. Watanabe S, Horie Y, Kataoka E, et al.

Non-alcoholic steatohepatitis and

hepatocellular carcinoma: lessons from

hepatocyte-specific phosphatase and tensin

homolog (PTEN)-deficient mice.

J Gastroenterol Hepatol

2007;22(Suppl 1):S96-S100

29. Caldwell S, Park SH. The epidemiology of

hepatocellular cancer: from the

perspectives of public health problem to

tumor biology. J Gastroenterol

2009;44(Suppl 19):96-101

30. Taub R. Liver regeneration: from myth to

mechanism. Nat Rev Mol Cell Biol

2004;5(10):836-47

31. Harada K, Shiota G, Kawasaki H.

Transforming growth factor-alpha and

epidermal growth factor receptor in

chronic liver disease and hepatocellular

carcinoma. Liver 1999;19(4):318-25

32. Hisaka T, Yano H, Haramaki M, et al.

Expressions of epidermal growth factor

family and its receptor in hepatocellular

carcinoma cell lines: relationship to cell

proliferation. Int J Oncol

1999;14(3):453-60

33. Ito Y, Takeda T, Higashiyama S, et al.

Expression of heparin binding epidermal

growth factor-like growth factor in

hepatocellular carcinoma: an

immunohistochemical study. Oncol Rep

2001;8(4):903-7

34. Huether A, Hopfner M, Baradari V, et al.

EGFR blockade by cetuximab alone or as

combination therapy for growth control of

hepatocellular cancer. Biochem Pharmacol

2005;70(11):1568-78

35. Hopfner M, Sutter AP, Huether A, et al.

Targeting the epidermal growth factor

Wysocki


Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y N

yu M

edic

al C

ente

r on

05/

13/1

3Fo

r pe

rson

al u

se o

nly.

receptor by gefitinib for treatment of

hepatocellular carcinoma. J Hepatol

2004;41(6):1008-16

36. Philip PA, Mahoney MR, Allmer C, et al.

Phase II study of erlotinib (OSI-774) in

patients with advanced hepatocellular

cancer. J Clin Oncol 2005;23(27):6657-63

37. Thomas MB, Chadha R, Glover K, et al.

Phase 2 study of erlotinib in patients with

unresectable hepatocellular carcinoma.

Cancer 2007;110(5):1059-67

38. Ramanathan RK, Belani CP, Singh DA,

et al. A phase II study of lapatinib in

patients with advanced biliary tree and

hepatocellular cancer.

Cancer Chemother Pharmacol

2009;64(4):777-83

39. O’Dwyer PJ, Giantonio BJ, Levy DE, et al.

Gefitinib in advanced unresectable

hepatocellular carcinoma: results from the

Eastern Cooperative Oncology Group’s

Study E1203. J Clin Oncol

(Meeting Abstracts)

2006;24(18 Suppl):4143

40. Zhu AX, Stuart K, Blaszkowsky LS, et al.

Phase 2 study of cetuximab in patients with

advanced hepatocellular carcinoma.

Cancer 2007;110(3):581-9

41. Gruenwald V, Wilkens L, Gebel M, et al.

A phase II open-label study of cetuximab in

unresectable hepatocellular carcinoma:

final results. J Clin Oncol

(Meeting Abstracts)

2007;25(18 Suppl):4598

42. Louafi S, Hebbar M, Rosmorduc O, et al.

Gemcitabine, oxaliplatin (GEMOX) and

cetuximab for treatment of hepatocellular

carcinoma (HCC): results of the phase II

study ERGO. J Clin Oncol

(Meeting Abstracts)

2007;25(18 Suppl):4594

43. Breuhahn K, Longerich T, Schirmacher P.

Dysregulation of growth factor signaling in

human hepatocellular carcinoma.

Oncogene 2006;25(27):3787-800

44. Rowinsky EK, Youssoufian H, Tonra JR,

et al. IMC-A12, a human IgG1

monoclonal antibody to the insulin-like

growth factor I receptor. Clin Cancer Res

2007;13(18 Pt 2):5549s-55s

45. Higano CS, Yu EY, Whiting SH, et al. A

phase I, first in man study of weekly

IMC-A12, a fully human insulin like

growth factor-I receptor IgG1 monoclonal

antibody, in patients with advanced solid

tumors. J Clin Oncol (Meeting Abstracts)

2007;25(18 Suppl):3505

46. Vivanco I, Sawyers CL. The

phosphatidylinositol 3-Kinase AKT

pathway in human cancer. Nat Rev Cancer

2002;2(7):489-501

47. Fang JY, Richardson BC. The MAPK

signalling pathways and colorectal cancer.

Lancet Oncol 2005;6(5):322-7

48. Giannelli G, Sgarra C, Porcelli L, et al.

EGFR and VEGFR as potential target for

biological therapies in HCC cells.

Cancer Lett 2008;262(2):257-64

49. Oseini AM, Roberts LR. PDGFRalpha: a

new therapeutic target in the treatment of

hepatocellular carcinoma? Expert Opin

Ther Targets 2009;13(4):443-54

50. Franovic A, Gunaratnam L, Smith K, et al.

Translational up-regulation of the EGFR

by tumor hypoxia provides a

nonmutational explanation for its

overexpression in human cancer. Proc Natl

Acad Sci USA 2007;104(32):13092-7

51. Xiao GH, Jeffers M, Bellacosa A, et al.

Anti-apoptotic signaling by hepatocyte

growth factor/Met via the

phosphatidylinositol 3-kinase/Akt and

mitogen-activated protein kinase

pathways. Proc Natl Acad Sci USA

2001;98(1):247-52

52. Wang L, Wang WL, Zhang Y, et al.

Epigenetic and genetic alterations of

PTEN in hepatocellular carcinoma.

Hepatol Res 2007;37(5):389-96

53. Villanueva A, Chiang DY, Newell P, et al.

Pivotal role of mTOR signaling in

hepatocellular carcinoma.

Gastroenterology

2008;135(6):1972-83, 83 e1-11

54. Rogers R, Ouellet G, Brown C, et al.

Cross-talk between the Akt and

NF-kappaB signaling pathways inhibits

MEHP-induced germ cell apoptosis.

Toxicol Sci 2008;106(2):497-508

55. Bellacosa A, Chan TO, Ahmed NN, et al.

Akt activation by growth factors is a

multiple-step process: the role of the PH

domain. Oncogene 1998;17(3):313-25

56. Schmitz KJ, Wohlschlaeger J, Lang H,

et al. Activation of the ERK and AKT

signalling pathway predicts poor prognosis

in hepatocellular carcinoma and ERK

activation in cancer tissue is associated with

hepatitis C virus infection. J Hepatol

2008;48(1):83-90

57. Sahin F, Kannangai R, Adegbola O, et al.

mTOR and P70 S6 kinase expression in

primary liver neoplasms. Clin Cancer Res

2004;10(24):8421-5

58. Faivre S, Kroemer G, Raymond E. Current

development of mTOR inhibitors as

anticancer agents. Nat Rev Drug Discov

2006;5(8):671-88

59. Liu H, Pan Z, Li A, et al. Roles of

chemokine receptor 4 (CXCR4) and

chemokine ligand 12 (CXCL12) in

metastasis of hepatocellular carcinoma

cells. Cell Mol Immunol 2008;5(5):373-8

60. Xiang ZL, Zeng ZC, Tang ZY, et al.

Chemokine receptor CXCR4 expression in

hepatocellular carcinoma patients increases

the risk of bone metastases and poor

survival. BMC Cancer 2009;9:176

61. Leufgen H, Bihl MP, Rudiger JJ, et al.

Collagenase expression and activity is

modulated by the interaction of collagen

types, hypoxia, and nutrition in human

lung cells. J Cell Physiol

2005;204(1):146-54

62. Erler JT, Bennewith KL, Nicolau M, et al.

Lysyl oxidase is essential for

hypoxia-induced metastasis. Nature

2006;440(7088):1222-6

63. Covello KL, Kehler J, Yu H, et al.

HIF-2alpha regulates Oct-4: effects of

hypoxia on stem cell function, embryonic

development, and tumor growth.

Genes Dev 2006;20(5):557-70

64. Gordan JD, Simon MC.

Hypoxia-inducible factors: central

regulators of the tumor phenotype.

Curr Opin Genet Dev 2007;17(1):71-7

65. Levitzki A. PDGF receptor kinase

inhibitors for the treatment of PDGF

driven diseases. Cytokine Growth

Factor Rev 2004;15(4):229-35

66. Semenza GL. Targeting HIF-1 for cancer

therapy. Nat Rev Cancer

2003;3(10):721-32

67. Amaravadi R, Thompson CB. The survival

kinases Akt and Pim as potential

pharmacological targets. J Clin Invest

2005;115(10):2618-24

68. Lee TK, Man K, Ho JW, et al. FTY720

induces apoptosis of human hepatoma cell

lines through PI3-K-mediated Akt

dephosphorylation. Carcinogenesis

2004;25(12):2397-405

69. Crul M, Rosing H, de Klerk GJ, et al.

Phase I and pharmacological study of daily

oral administration of perifosine

(D-21266) in patients with advanced solid



Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y N

yu M

edic

al C

ente

r on

05/

13/1

3Fo

r pe

rson

al u

se o

nly.

tumours. Eur J Cancer

2002;38(12):1615-21

70. Van Ummersen L, Binger K, Volkman J,

et al. A phase I trial of perifosine (NSC

639966) on a loading dose/maintenance

dose schedule in patients with advanced

cancer. Clin Cancer Res

2004;10(22):7450-6

71. Liu F, Wang P, Jiang X, et al. Antisense

hypoxia-inducible factor 1alpha gene

therapy enhances the therapeutic efficacy of

doxorubicin to combat hepatocellular

carcinoma. Cancer Sci

2008;99(10):2055-61

72. Semela D, Piguet AC, Kolev M, et al.

Vascular remodeling and antitumoral

effects of mTOR inhibition in a rat model

of hepatocellular carcinoma. J Hepatol

2007;46(5):840-8

73. Huynh H, Chow KH, Soo KC, et al.

RAD001 (everolimus) inhibits tumour

growth in xenograft models of human

hepatocellular carcinoma. J Cell Mol Med

2009;13(7):1371-80

74. Pang RW, Poon RT. From molecular

biology to targeted therapies for

hepatocellular carcinoma: the future is

now. Oncology 2007;72(Suppl 1):30-44

75. Rizell M, Andersson M, Cahlin C, et al.

Effects of the mTOR inhibitor sirolimus in

patients with hepatocellular and

cholangiocellular cancer. Int J Clin Oncol

2008;13(1):66-70

76. Lev S, Moreno H, Martinez R, et al.

Protein tyrosine kinase PYK2 involved in

Ca(2+)-induced regulation of ion channel

and MAP kinase functions. Nature

1995;376(6543):737-45

77. Dhillon AS, Hagan S, Rath O, Kolch W.

MAP kinase signalling pathways in cancer.

Oncogene 2007;26(22):3279-90

78. McKillop IH, Schmidt CM, Cahill PA,

Sitzmann JV. Altered expression of

mitogen-activated protein kinases in a rat

model of experimental hepatocellular

carcinoma. Hepatology

1997;26(6):1484-91

79. Schmidt CM, McKillop IH, Cahill PA,

Sitzmann JV. Increased MAPK expression

and activity in primary human

hepatocellular carcinoma.

Biochem Biophys Res Commun

1997;236(1):54-8

80. Giambartolomei S, Covone F, Levrero M,

Balsano C. Sustained activation of the Raf/

MEK/Erk pathway in response to EGF in

stable cell lines expressing the Hepatitis C

Virus (HCV) core protein. Oncogene

2001;20(20):2606-10

81. Lee HC, Tian B, Sedivy JM, et al. Loss of

Raf kinase inhibitor protein promotes cell

proliferation and migration of human

hepatoma cells. Gastroenterology

2006;131(4):1208-17

82. Coleman WB. Mechanisms of human

hepatocarcinogenesis. Curr Mol Med

2003;3(6):573-88

83. Carloni V, Vizzutti F, Pantaleo P.

Farnesyltransferase inhibitor, ABT-100, is

a potent liver cancer chemopreventive

agent. Clin Cancer Res

2005;11(11):4266-74

84. Wentz SC, Wu H, Yip-Schneider MT,

et al. Targeting MEK is effective

chemoprevention of hepatocellular

carcinoma in TGF-alpha-transgenic mice.

J Gastrointest Surg 2008;12(1):30-7

85. Huynh H, Soo KC, Chow PK, Tran E.

Targeted inhibition of the extracellular

signal-regulated kinase kinase pathway

with AZD6244 (ARRY-142886) in the

treatment of hepatocellular carcinoma.

Mol Cancer Ther 2007;6(1):138-46

86. Llovet JM, Ricci S, Mazzaferro V, et al.

Sorafenib in advanced hepatocellular

carcinoma. N Engl J Med

2008;359(4):378-90

87. Cheng AL, Kang YK, Chen Z, et al.

Efficacy and safety of sorafenib in patients

in the Asia-Pacific region with advanced

hepatocellular carcinoma: a phase III

randomised, double-blind,

placebo-controlled trial. Lancet Oncol

2009;10(1):25-34

88. Poon RT, Ng IO, Lau C, et al. Tumor

microvessel density as a predictor of

recurrence after resection of hepatocellular

carcinoma: a prospective study.

J Clin Oncol 2002;20(7):1775-85

89. Yao DF, Wu XH, Zhu Y, et al.

Quantitative analysis of vascular

endothelial growth factor, microvascular

density and their clinicopathologic features

in human hepatocellular carcinoma.

Hepatobiliary Pancreat Dis Int

2005;4(2):220-6

90. Yoshiji H, Kuriyama S, Yoshii J, et al.

Vascular endothelial growth factor tightly

regulates in vivo development of murine

hepatocellular carcinoma cells. Hepatology

1998;28(6):1489-96

91. Park YN, Kim YB, Yang KM, Park C.

Increased expression of vascular endothelial

growth factor and angiogenesis in the early

stage of multistep hepatocarcinogenesis.

Arch Pathol Lab Med 2000;124(7):1061-5

92. Zhao J, Hu J, Cai J, et al. Vascular

endothelial growth factor expression in

serum of patients with hepatocellular

carcinoma. Chin Med J (Engl)

2003;116(5):772-6

93. Huang GW, Yang LY, Lu WQ. Expression

of hypoxia-inducible factor 1alpha and

vascular endothelial growth factor in

hepatocellular carcinoma: impact on

neovascularization and survival.

World J Gastroenterol

2005;11(11):1705-8

94. Imura S, Miyake H, Izumi K, et al.

Correlation of vascular endothelial cell

proliferation with microvessel density and

expression of vascular endothelial growth

factor and basic fibroblast growth factor in

hepatocellular carcinoma. J Med Invest

2004;51(3-4):202-9

95. Moon WS, Rhyu KH, Kang MJ, et al.

Overexpression of VEGF and angiopoietin

2: a key to high vascularity of

hepatocellular carcinoma? Mod Pathol

2003;16(6):552-7

96. Liu Y, Poon RT, Li Q, et al. Both

antiangiogenesis- and

angiogenesis-independent effects are

responsible for hepatocellular carcinoma

growth arrest by tyrosine kinase inhibitor

PTK787/ZK222584. Cancer Res

2005;65(9):3691-9

97. Finn RS, Bentley G, Britten CD, et al.

Targeting vascular endothelial growth

factor with the monoclonal antibody

bevacizumab inhibits human

hepatocellular carcinoma cells growing in

an orthotopic mouse model. Liver Int

2009;29(2):284-90

98. Siegel AB, Cohen EI, Ocean A, et al.

Phase II trial evaluating the clinical and

biologic effects of bevacizumab in

unresectable hepatocellular carcinoma.

J Clin Oncol 2008;26(18):2992-8

99. Boige V, Baey C, Dromain C, et al.

Circulating endothelial cells (CEC) and

angiogenic proteins monitoring in patients

(pts) with advanced hepatocellular

carcinoma (HCC) treated with

bevacizumab. J Clin Oncol

(Meeting Abstracts) 2009;27(15S):4597

100. Thomas MB, Morris JS, Chadha R, et al.

Phase II trial of the combination of

Wysocki


Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y N

yu M

edic

al C

ente

r on

05/

13/1

3Fo

r pe

rson

al u

se o

nly.

bevacizumab and erlotinib in patients who

have advanced hepatocellular carcinoma.

J Clin Oncol 2009;27(6):843-50

101. Zhu AX, Blaszkowsky LS, Ryan DP, et al.

Phase II study of gemcitabine and

oxaliplatin in combination with

bevacizumab in patients with advanced

hepatocellular carcinoma. J Clin Oncol

2006;24(12):1898-903

102. Sun W, Haller DG, Mykulowycz K, et al.

Combination of capecitabine, oxaliplatin

with bevacizumab in treatment of

advanced hepatocellular carcinoma

(HCC): a phase II study. J Clin Oncol

(Meeting Abstracts)

2007;25(18 Suppl):4574

103. Hsu C, Yang T, Toh H, et al.

Modified-dose capecitabine + bevacizumab

for the treatment of advanced/metastatic

hepatocellular carcinoma (HCC): a

phase II, single-arm study. J Clin Oncol

(Meeting Abstracts)

2007;25(18 Suppl):15190

104. Wysocki PJ, Zolnierek J, Szczylik C,

Mackiewicz A. Targeted therapy of renal

cell cancer. Curr Opin Investig Drugs

2008;9(6):570-5

105. Koeberle D, Montemurro M, Samaras P,

et al. Continuous sunitinib treatment in

patients with unresectable hepatocellular

carcinoma (HCC): a multicenter phase II

trial (SAKK 77/06 and SASL 23). J Clin

Oncol (Meeting Abstracts)

2009;27(15S):4591

106. Zhu AX, Sahani DV, Duda DG, et al.

Efficacy, safety, and potential biomarkers

of sunitinib monotherapy in advanced

hepatocellular carcinoma: a phase II study.

J Clin Oncol 2009;27(18):3027-35

107. Raoul JL, Finn RS, Kang YK, et al. An

open-label phase II study of first- and

second-line treatment with brivanib in

patients with hepatocellular carcinoma

(HCC). J Clin Oncol (Meeting Abstracts)

2009;27(15S):4577

108. Abou-Alfa GK, Schwartz L, Ricci S, et al.

Phase II study of sorafenib in patients with

advanced hepatocellular carcinoma.

J Clin Oncol 2006;24(26):4293-300

109. Strebel BM, Dufour JF. Combined

approach to hepatocellular carcinoma: a

new treatment concept for nonresectable

disease. Expert Rev Anticancer Ther

2008;8(11):1743-9

AffiliationPiotr Jan Wysocki MD PhD

Chair of Medical Biotechnology,

University of Medical Sciences,

Department of Chemotherapy,

Greater Poland Cancer Center,

ul. Garbary 15, Poznan 61-866, Poland

Tel: +48 61 885 0620; Fax: +48 61 885 0694;

E-mail: [email protected]



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Documents

Targeted therapy of hepatocellular cancer