Novel molecular therapies in hepatocellular carcinoma

Novelmolecular therapies in hepatocellular carcinomaSandrine Faivre, Mohamed Bouattour and Eric Raymond

Department of Medical Oncology, Beaujon/Bichat University Hospital, Assistance Publique-Hopitaux de Paris, University INSERM U728, Paris 7, Clichy,

France

Keywords

angiogenesis inhibitors – clinical trial –

hepatocellular carcinoma – targeted therapies

Abbreviations

HCC, hepatocellular carcinoma; PDGFR,

platelet-derived growth factor receptor; SOC,

standard of care; VEGF, vascular endothelial

growth factor.

Correspondence

Eric Raymond, MD, PhD, Department of

Medical Oncology, Beaujon/Bichat University

Hospital, Assistance Publique-Hopitaux de Paris,

University INSERM U728, Paris 7 Diderot, 100

boulevard du General Leclerc, 92110 Clichy,

France

Tel: 133 1 40 87 56 14

Fax: 133 1 40 87 54 87

e-mail: [email protected]

Received 10 November 2010

Accepted 26 November 2010

DOI:10.1111/j.1478-3231.2010.02395.x

AbstractThe approval of sorafenib as the standard of care (SOC) for advancedhepatocellular carcinoma (HCC) fostered interest to further evaluate severalother targeted therapies and extend the positioning of sorafenib alone and incombination with other drugs and local therapies at earlier stages and in anadjuvant setting. This review highlights current research using targetedtherapies in HCC. Information for this review was compiled by searchingPubMed and MEDLINE databases for articles published until September2010. Several small molecules and humanized antibodies with anti-angiogenicand antiproliferative properties are currently being investigated in preclinicaland/or clinical trials. Results are awaited from these clinical trials and offerpromise for extending the current treatment options in HCC. Currentlypublished data suggest that substantial progress may be achieved in thetreatment of patients with HCC in the next 10 years.

Chemotherapy, including single agent doxorubicin, mul-tidrug regimens such as platinum–ifospahmide–adria-mycin–5FU and more recently platinum-based doubletssuch as GEMOX (gemcitabin and oxaliplatin) or FOL-FOX (5fluorouracil and oxaliplatin), has long been themainstay standard of care in patients with advancedhepatocellular carcinoma (HCC). Although activity hasbeen suggested in a number of case reports and smallclinical trials, none of those regimens has demonstratedan improvement in overall survival (OS) (1). Only onerecent clinical study showed that FOLFOX improved theOS compared with doxorubicin in Asian patients (2).Sorafenib is the first targeted therapy shown to improvesurvival and has led to therapeutic options for HCC.Furthermore, improved understanding of tumour biol-ogy and critical signalling pathways in HCC have sug-gested that several key kinases may be targets for novelanticancer agents.

The aim of this review was to discuss the use of theseemerging drugs in HCC and, in particular, the challengesof clinical development.

Drug targets in hepatocellular carcinoma

The carcinogenesis of HCC is heterogeneous andcomplex (3). Several critical signalling pathways andmolecular disturbances involved in the development ofHCC and tumour invasion have been described exten-sively. The genetic disturbances and disrupted signallingpathways involved in the proliferation, survival, differ-entiation, invasion and metastasis of HCC cells have beenreviewed elsewhere (4–7).

Hepatocellular carcinoma is one of the most vascular-ized solid cancers, associated with a high tendencytowards vascular invasion. Immunohistochemical stu-dies showed that increased microvessel density wasassociated with a poor outcome after surgery and corre-lated with a risk of vascular invasion, metastasis and apoor prognosis (8). Vascular endothelial growth factor(VEGF) is the principal mediator of angiogenesis in HCC(9–11). Most HCC overexpress VEGF and have anaberrant VEGF expression (9–12). High VEGF expres-sion has been associated with decreased survival (9).

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Research has primarily targeted pro-angiogenic growthfactors such as VEGF (using bevacizumab) or membranetyrosine kinase receptors such as vascular endothelialgrowth factor receptor (VEGFR) (using sorafenib, suni-tinib, brivanib and others). Other pro-angiogenic factorssuch as platelet-derived growth factor receptor (PDGFR)and basic fibroblast growth factor receptor FGF (bFGF;FGF-2) have been shown to play crucial roles in HCCangiogenesis, making them attractive candidates fortargeted therapies.

The epidermal growth factor receptor (EGFR) is over-expressed in 40–70% of HCC, and proliferation wasshown to be dependent on stimulation of EGFR bytransforming growth factor (TGF)-a or EGF in severalHCC cells (13). Thus, targeting EGFR is a logical optionfor the treatment of HCC. The results of preclinicalmodels of therapeutic approaches using neutralizingantibodies against EGFR (cetuximab or panitumumab)or small-molecule EGFR tyrosine kinase inhibitors(gefitinib, erlotinib and lapatinib) have been interesting(14, 15).

The phosphatidylinositol 3-kinase (PI3K)/Akt/mam-malian target of the rapamycin (mTOR) pathway wasshown to be crucial in HCC cell survival in severalpreclinical models. This pathway was responsible fordownstream cell signalling of various tyrosine kinasereceptors, such as VEGFR, EGFR, PDGFR and IGF-1R.Genomic studies indicate that about 50% of patientswith HCC have mTOR signalling disturbances (16). InHCC, the activation of the PI3K/Akt/mTOR pathway isassociated with a poor prognosis (17). This pathway canbe targeted at various levels but at present, mTORinhibitors such as rapamycin or its analogues (ever-olimus and temsirolimus) are the main available options.

Sorafenib: a validated proof of concept fortargeted therapy

Sorafenib (Bayer Pharmaceuticals Corporation, Leverku-sen, Germany) is an oral multityrosine kinase inhibitortargeting the intracellular serine/threonine Raf kinase,the VEGFR-2 and -3, PDGFR-b, Fms-like tyrosine kinase3 (Flt-3). In HCC cell lines and xenograft models,sorafenib has been shown to prevent tumour cell growthand induce apoptosis as well as anti-angiogenic effects(18, 19). Sorafenib is the first and only drug so far shownto improve the OS in patients with advanced HCC in twolarge multicentre, double-blind, placebo-controlled ran-domized phase III trials (20, 21). These two large trialswere performed based on promising results from a phaseII study (22). In the western trial, the benefit of sorafenibin the European-American population was the result ofan increase in the median OS from 7.9 months in theplacebo group to 10.7 months in the sorafenib group(HR = 0.69; 95% CI 0.55–0.87; P = 0.00058). Sorafenibextended the OS by 44%, and decreased the relative riskof death by 31% (20). The same increase in survival wasconfirmed in the Asian-Pacific population that had more

advanced disease and in whom hepatitis B infection wasthe prevalent cause of cirrhosis. The median OS was 6.5months in the sorafenib group versus 4.2 months in theplacebo group (HR = 0.68; 95% CI 0.500.93; P = 0.014)(21). Tolerance to sorafenib in these two studies wasgenerally good. The most common grade 3 drug-relatedadverse events in the Sorafenib HCC Assessment Rando-mized Protocol and Asian-Pacific studies, includingdiarrhoea and hand–foot skin reaction, occurred ino 10% of patients. Noticeably, the incidence of bleedingwas similar in the experimental and the placebo arms(20). Based on these data, the United States (US) Foodand Drug Administration (FDA), European MedicineAgency (EMA) and other regulatory authorities in theworld approved sorafenib for advanced HCC.

Anti-angiogenic agents in clinical development

Sunitinib (SU011248, Pfizer Inc., New York, USA) –sunitinib malate is another oral multityrosine kinasetargeting the VEGFR-1, -2, PDGFR-a, -b, c-Kit, Flt-3and RET. Sunitinib was identified in a drug discoveryprogramme designed to identify more potent VEGFRsand PDGFRs inhibitors (23), which, as described above,play important roles in the angiogenesis of HCC. Suniti-nib has already been approved for the treatment of renalcell carcinoma as well as gastrointestinal stromal tu-mours that are refractory or intolerant to imatinib.Recently, in a placebo-controlled randomized phase IIItrial, this compound was shown to exert a significantclinical benefit on progression-free survival (PFS) andsafety in patients with advanced pancreatic endocrinetumours, another hypervascularized tumour (24). Inxenograft models of HCC, sunitinib induced tumourgrowth inhibition by increasing apoptosis, reducingmicrovessel density and inhibiting cell proliferation(25). The results of three previous independent phase IIstudies on the efficacy and tolerance of sunitinib inpatients with advanced HCC were encouraging (26–28).In the European/Asian study, a low response rate wasobtained despite the marked antitumour activity because35% of patients treated with 50 mg/day sunitinib(4 weeks on/2 weeks off) achieved stable disease for over3 months, resulting in disease control of 37.8% (26).Similar results were observed with the use of sunitinib atthe dose of 37.5 mg/day with the same schedule becausestable disease was reported in 50% of patients (27). Themedian OS was 8 and 9.8 months respectively (26, 27).More recently, the results of a Swiss phase II study with acontinuous daily dose of sunitinib of 37.5 mg showed aPFS at 12 weeks in 33% of patients. The median OS was9.3 months (28). A multinational, phase III study(NCT00699374) comparing sunitinib with sorafenib inpatients with advanced HCC was discontinued on 22April 2010, because of a higher incidence of seriousadverse events in the sunitinib arm than the sorafenibarm, and because sunitinib did not meet the primaryendpoint in the overall population. The details of this

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Targeted therapies in HCC Faivre et al.

trial will soon be available. The dosing and schedules ofsunitinib seem to be complex in patients with HCC (29).Frequent underlying liver disease generate a narrowtherapeutic index and the routine daily dose of 50 mgused in other tumour types does not seem to be suitablein these patients (30).

Brivanib (BMS-582664; Bristol-Meyers Squibb, NewYork, USA) – brivanib alaninate is a potent, oral, selectiveinhibitor of VEGFR-2, -3 and FGFR-2, -3, tyrosinekinases. FGFR inhibition could provide an add-on ben-efit in HCC compared with VEGFR/PDGFR inhibitors.In derived HCC xenografts, brivanib significantly sup-pressed tumour growth, resulting in decreased meanblood microvessel density as well as increased apoptosisand a reduction in microvessel density (31). Similarresults were reported in a broad range of human tumourxenografts, encompassing models of chemoresistant dis-ease. Assessment of angiogenesis by dynamic contrast-enhanced MRI showed a significant reduction in tumourvascular density and in blood flow (32). Brivanib(800 mg daily) as either a first-line or a second-linetherapy was evaluated in a phase II open-label study inpatients with advanced HCC. Interim efficacy and safetyresults were reported at ASCO 2009 (33) and updated atILCA 2009 (34). The median OS was 10 months in thefirst-line treated group and 9.8 months in the second-linetreated group (including prior treatment with sorafenib).Major grade Z3 toxicities were fatigue (16%), hypona-traemia (15%) and hypertension (11%). Based on theseresults and evidence of antitumour activity, brivanib iscurrently being evaluated in phase II trials in patientswith advanced HCC as a first-line treatment comparedwith sorafenib (NCT00858871) as a second-line therapycompared with placebo (NCT00825955) and also com-pared with placebo as an adjuvant therapy to transarter-ial chemo-embolization (NCT00908752).

Linifanib (ABT-869, Abbott, Abbott Park, USA) –linifanib is a novel, orally bioavailable, small-moleculereceptor tyrosine kinase inhibitor that targets VEGF andPDGF receptor families. In a phase I study, linifanib wasfound to be well tolerated at doses � 0.25 mg/kg daily.After 17 months in the cohort of 33 patients with HCC,prolonged stable disease was achieved in two patientswith HCC. Dynamic radiological assessment showedreduced vascular permeability of the tumour and vascu-larity correlated to drug exposure (35). Recently, interimresults of an open-label multicentre phase II trial of ABT-869 in patients with advanced HCC were reported (34).ABT-869 was administered at 0.25 mg/kg daily to Child-Pugh (CP) class A patients or every other day in CP classB patients. Thirty-four patients could be evaluated in thiscohort, and an objective response was achieved in 8.7%of CP class A patients but in none of the CP class Bpatients. The median TTP was 112 days and the medianOS was 295 days. The most common grade Z3 toxicitieswere hypertension (20.6%) and fatigue (11.8%). Up-dated results showed a clinical benefit in CP class Apatients with a median TTP of 5.4 months and a median

OS of 10.4 months. The benefit appears to be limited inpatients with CP class B because the median TTP was 3.7months and the median OS was 2.5 months (37). Basedon these encouraging results, the efficacy and tolerance ofa daily dose of 17.5 mg linifanib is now being comparedwith that of sorafenib in an international randomizednon-blinded phase III study in patients CP class A andadvanced HCC (NCT01009593).

Axitinib (AG-013736; Pfizer Inc.) – axitinib is a potentinhibitor of VEGFR tyrosine kinase, PDGFR and Kit.Axitinib had been shown to have potent preclinicalactivity in various models (38). Interestingly, no cross-resistance has been found between axitinib and otheragents because the antitumour activity of axitinib wasreported in patients with metastatic RCC in whomtreatment with sunitinib, sorafenib and cytokines thera-pies were unsuccessful (39). A combined phase II/III trialevaluating axitinib as a second-line agent in advancedHCC is being planned.

Cediranib (AZD2171, AstraZeneca, Wilmington, USA)– AZD2171, a potent oral small-molecule pan-VEGFRinhibitor that blocks PDGFR and c-Kit, has been shownto have antitumour activity in a broad range of humantumour xenograft models. Oral daily doses of 45 mg orless of AZD2171 were generally well tolerated andassociated with encouraging antitumour activity in awide variety of advanced solid tumours (40). AZD2171has been tested in a two-stage phase II study in patientswith non-resectable HCC. At the dose of 45 mg/day, 84%of the evaluated patients experienced grade 3 toxicitiesincluding fatigue, hypertension and anorexia (41). Poortolerance to this agent could be due in part to underlyingcirrhosis because liver metabolism could be impaired byliver dysfunction. Thus, another phase II study wasplanned with a reduced dose of AZD2171. However, thisstudy has been suspended (NTC00427973).

TSU-68 (SU6668, Taiho Pharmaceutical Co. Ltd,Tokyo, Japan) – TSU-68 is an oral multikinase inhibitorof VEGFR-2, PDGFR and FGFR. This compound hasbeen assessed in 35 Japanese patients with CP classes A/BHCC in a coupled phase I/II study (42). Two hundredmilligrams of STU-68 was administered twice a day. Inthis study, 11.4% of patients experienced grade 3/4adverse events including elevated AST/ALT levels andthrombocytopenia. An objective response was observedin 9.6% of patients (complete response: 2.9% and partialresponse: 5.7%). Stable disease was achieved in 42.8% ofpatients. The median PFS was 2.1 months compared witha surprising median OS of 13.1 months (42).

Pazopanib (GW786034, GlaxoSmithKline, Brentford,UK) – pazopanib is an oral, multitargeted tyrosine kinaseinhibitor that targets VEGFRs, PDGFR and c-Kit. Thiscompound recently obtained US FDA approval for thetreatment of advanced renal cell carcinoma. Pazopanibwas evaluated in a phase I study in patients withadvanced HCC (43). The maximum tolerated dosewas established as 600 mg twice a day. The main grade3/4-related side effects were diarrhoea (4%) and


Faivre et al. Targeted therapies in HCC

hypertension (26%). Partial response and stable diseasewere observed in 7.5 and 41% of patients respectively.Thus, pazopanib appears to be a promising active drugfor further clinical development in HCC.

Vandetanib (ZD6474, AstraZeneca, Wilmington,USA) – ZD6474 is an orally active inhibitor of VEGFR,EGFR and RET tyrosine kinases. In preclinical modelsand under experimental conditions, ZD6474 was shownto inhibit HCC cell proliferation adhesion, migrationand invasion (44). ZD6474 is currently being evaluatedin a phase II trial in patients with advanced HCC(NCT00508001).

Vatalanib (PTK787/ZK, Novartis, Basel, Switzerlandand Bayer Schering Pharma) – PTK787 is an orally active,selective inhibitor of all VEGFR tyrosine kinases. Athigher concentrations, this compound also inhibits othertyrosine kinases such as PDGFR and Kit. PTK787 in-duced tumour cell apoptosis and reduced vessel forma-tion. Its effect was enhanced by the induction of hypoxiathrough ligation of the hepatic artery (45), which sug-gests that this compound might be interesting in combi-nation with transarterial chemoembolization. In thephase I study, the maximum tolerated dose was 750 mgdaily and stable disease was observed in 50% of patients(46). For pharmacological and marketing reasons, thedevelopment of PTK787/ZK was not pursued in HCC.

BIBF 1120 (Vargatef, Boehringer Ingelheim, Ridge-field, Germany) – BIBF 1120 is an oral triple angiokinaseinhibitor targeting VEGF, FGFR and PDGF receptorsthat showed antitumour activity in preclinical models(47). Its activity on FGFR was considered to be apotential advantage to broaden its activity over otherVEGFR inhibitors. This compound is being comparedwith sorafenib in two different phase II studies toevaluate the safety and the efficacy for advanced HCC inEuropean patients (NCT01004003) and Asian patients(NCT00987935).

Foretinib (GSK1363089, EXEL-2880; XL-880, Exelixis,San Francisco, USA) – foretinib is an orally bioavailableselective inhibitor of c-Met and VEGFR-2 tyrosine ki-nases. Targeting the c-Met pathway could be a potentialtherapy in HCC because dysregulation of c-MET as wellas its ligand HGF are frequent (48) and overexpression ofc-Met correlates with more advanced HCC (49). Theexact role of this pathway in the pathogenesis of HCC hasnot been clearly elucidated. Blocking the HGF/c-METpathway during the orthotopic transplant of HCC mod-els induced growth suppression and a decrease in angio-genesis (50). Foretinib was found to be potentially activein preclinical HCC models with inhibition of tumourangiogenesis, tumour cell proliferation and metastasis(51). Although several molecules targeting MET path-ways are under development (52), only foretinib is beinginvestigated for safety and tolerance in patients withadvanced HCC in a phase I/II study (NCT00920192).

Bevacizumab (Genentech Inc., San Francisco, USAand Roche, Basel, Switzerland), a recombinant, huma-nized monoclonal antibody directed against all VEGF

isoforms, has emerged as an important therapeutic agent.It has been approved for the treatment of several carci-nomas including colorectal, non-small-cell lung, breastcancer and metastatic renal cell carcinoma. In preclinicalmodels of HCC, bevacizumab induced a significantdecrease in vessel density and prolonged time to progres-sion of tumour-bearing mice (53). Bevacizumab wasevaluated as a single agent for the treatment of advancedHCC in two phase II trials. In the first study in 46patients with locally advanced HCC, partial responseswere observed in 13% and disease stabilization for at least6 months was obtained in 65% of patients, with a medianPFS of 6.9 months (54). The OS rate at 1, 2 and 3 yearswas 53, 28 and 23% respectively. Comparable results werereported in the interim results of a French study, becausepartial response and stable disease for at least 16 weekswere observed in 12.5 and 29 % respectively (55).Updated data presented at ASCO 2009 showed thatbevacizumab induced 16% partial response and 47%stable disease in 38 patients (56). Despite these promisingresults, it should be noted that patients with a CLIP score4 3 (55), liver involvement of the tumour of 4 50%and/or with vascular invasion and/or extrahepatic spreaddisease (54) were excluded from trials. Therefore, it isdifficult to compare these results with those obtainedwith sorafenib and probably only well-selected patientscan benefit from this therapy. Moreover, these resultswere accompanied by a high incidence of adverse drug-related events, in particular, severe bleeding, whichoccurred in 11% of patients in the American study (54)and required withdrawal of the drug in 20% of patients inthe French study (55). Other serious side effects includedarterial thrombosis (6%) and hypertension (15%).

The combination of bevacizumab with cytotoxic agentswas also evaluated in phase II studies and was shown to bereasonably safe, with a moderate clinical benefit (57–59).The combination of bevacizumab and GEMOX was eval-uated in a phase II study. Twenty per cent of the 33 patientsenrolled showed an objective response. The median OS was9.6 months (57). Adding bevacizumab did not markedlyimprove the clinical benefit because results with GEMOXalone were similar in a phase II study, with a response rateof 18% and a median OS of 11.5 months (60).

Anti-epidermal growth factor receptor underclinical development

Cetuximab (C225, ImClone Systems, New York, USAand Merck Serono, Darmstadt, Germany), a chimericmonoclonal antibody directed against EGFR, is alreadypart of standard therapy in patients with metastaticcolorectal cancer and head neck cancer. Cetuximab wasevaluated as a single agent in two phase II studies (61,62). In the first study, no clinical responses were observedand stable disease was achieved in 17% of patients. Themedian OS was 9.6 months and the median PFS was 1.4months (61). In the second open-label study, stabledisease was observed for at least 8 weeks in 44.4% of the



cases and the median PFS was 1.8 months (62). Theresults of these two studies are inconsistent; hence, therole and activity of this compound in HCC must still beclarified. Currently, anti-EGFR-based approaches arebeing tested in clinical trials (NCT00142428), especiallyin combination with conventional chemotherapy(NCT00483405).

Erlotinib (OSI-774, Genentech Inc. and Roche) is apotent oral and specific inhibitor of the EGFR/HER1-related tyrosine kinase domain. Erlotinib is already ap-proved for the treatment of metastatic or locally advancednon-small-cell lung cancer and pancreatic cancer. Thesafety and efficacy of erlotinib as a single agent in Child-Pugh class A and B patients with advanced HCC werereported in two phase II clinical studies. The first reportshowed that 32% of patients were progression-free at 6months, with disease control in 59% of cases. The medianOS for this cohort was 13 months (63). The most frequentgrade 3/4 toxicities were skin rash, diarrhoea and fatigue.Treatment was significantly less well tolerated in CP class Bpatients (63). These results are limited by the fact that 42%of enrolled patients had no underlying liver disease. In thesecond study, erlotinib was evaluated in 40 patients with CPclass A or B cirrhosis and advanced HCC. There was nopartial or complete response to erlotinib. However, the PFSat 4 months was 43%, and the median OS was 10.75months. No correlation was found in this trial betweenEGFR expression and OS (64). A phase III clinical trial isongoing to evaluate the benefit of combining erlotinib withsorafenib compared with sorafenib plus placebo as a first-line therapy in patients with advanced HCC(NCT00901901). The results of a phase II study combiningbevacizumab and erlotinib were interesting, with a mediantime to progression of 9 months and a median OS of 15.65months. Major side effects included fatigue (20%), hyper-tension (15%) and gastrointestinal bleeding (12.5%) (65).Patients included in this study had slightly less advanceddisease than the populations in other published phase IItrials in this setting. Further studies are needed to confirmthe potential synergistic activity of this combination. Thiscombination is being compared with sorafenib as a first-line therapy in a phase 2 study (NCT00881751) as well as asecond-line therapy (NCT01180959).

Gefitinib (ZD1839, AstraZeneca), another EGFR tyr-osine kinase inhibitor, was also evaluated in a two-stagedesign, single-arm phase 2 study in patients with HCC(66). Thirty-one patients were recruited in the first stage.Gefitinib induced an objective response of 3% anddisease stabilization of 22.6%. The median PFS was 2.8months and the median OS was 6.5 months. Because thecriterion for the second stage of the study was not met,the authors hypothesized that gefitinib was not active as asingle agent in patients with advanced HCC (66).These results could be explained by the possible cross-talk between insulin-like growth factor 1 receptor(IGF-1R) and EGF signalling pathways (67). Gefitinibresistance may be associated with alternative activation ofthe IGF-2/IGF-1R survival pathway. Substitution

pathways could be developed by the tumour to bypassthe EGF signal for its survival and cell proliferation (67,68). A possible solution to avoid this resistance mechan-ism is to combine IGF-1R inhibitors and EGFR blockersand enhance the antitumour activity of the respectivemonotherapies (69, 70).

Lapatinib (GW572016, GlaxoSmithKline) is a selectivedual inhibitor of both EGFR and Human EGFR type 2(HER-2/NEU) signalling pathways. Although HER-2/NEU overexpression is rare in HCC, this compound hasalso been evaluated in advanced HCC. Twenty-six patientswith advanced HCC were treated with daily lapatiniborally at a dose of 1500 mg in a phase II study (71). Noobjective responses were obtained. Approximately 40% ofpatients achieved their best response. The median PFS andOS were 1.9 and 12.6 months respectively. Only threepatients experienced grade 3 drug-related toxicities in-cluding diarrhoea, rash and acute renal failure. Interest-ingly, patients who developed a rash (an effect of EGFR/HER1 inhibition) had a more favourable outcome withlonger survival compared with the overall study popula-tion (71). In another phase II study, a cohort of 40 patientswith advanced HCC was treated with lapatinib. Moderateantitumoral activity was observed because an objectiveresponse was observed in 5% of patients. The median PFSwas 2.3 and the median OS was 6.2 months (72).

mTOR inhibitors

Rapamycin (sirolimus) is an mTOR kinase inhibitor withantiproliferative (by inhibiting tumour cell growth andproliferation) and anti-angiogenesis activities (by bothdirect effects on vascular cell proliferation and indirecteffects on growth factor production). Rapamycin alsoinhibits VEGF secretion and signal transduction inducedby VEGF in endothelial cells ultimately altering tumourgrowth by an anti-angiogenic mechanism. Even if thePI3K/AKT/mTOR pathway could be inhibited at variouslevels, the most promising target in this pathway ismTOR. Rapamycin and its derivatives such as everolimus(RAD001, Novartis) yielded interesting antitumour ac-tivity in preclinical studies and xenograft models of HCC(73, 74). Two small pilot studies showed promisingresults on the efficacy of sirolimus in HCC patients witha safe profile (75, 76). The efficacy of sirolimus wasevaluated in a single-arm study in 21 advanced HCCpatients (75). Sirolimus induced a partial response andtumour stabilization for at least 3 months in 5 and 24%of patients respectively. The median OS was 6.5 months.No major sirolimus-related side effects were observed inthis study (75). In the French pilot study, 14 patientswere treated with 30 mg oral sirolimus once a week (76).A complete or a partial response according to theRECIST criteria was observed in 7 and 33% of patientsrespectively. Sirolimus also seemed to be safe because nograde 4 toxicity was observed and only two patientsexperienced grade 3 mucositis. Sirolimus did not affectliver function (76). Several phase I and phase II studies



are currently testing mTOR inhibitors as single agents(NCT00390195 and NCT00516165), in combinationwith sorafenib (NCT01008917) or with bevacizumab(NTC00775073). Based on the safety profile in patientswith cirrhosis temsirolimus (CCI-779, Pfizer Inc.) is alsobeing evaluated in a phase II study in CP class B patientswith advanced HCC (NCT01079767). Everolimus isbeing evaluated in patients with advanced HCC withprogressive disease or as a second-line therapy in a phaseIII study compared with placebo either following sorafe-nib or in patients who cannot tolerate sorafenib.

MEK/ERK inhibitors

The Raf/MEK/ERK pathway appears to be one of themost significant cellular signalling sequences in thedevelopment and maintenance of HCC (77). AZD6244(ARRY-142886, AstraZeneca) is an oral, new MEK in-hibitor. This compound combined with rapamycin hadbeen shown to have antitumour and anti-angiogeniceffects in preclinical models of human HCC (78).Furthermore, pharmacological inhibition of the MEK/ERK pathway by the MEK inhibitor AZD6244 enhancedthe antitumour effect of sorafenib in both orthotopic andectopic models of HCC (79). However, AZD6244 as asingle agent did not show any clinical benefit. Indeed,this compound was evaluated in 19 patients with ad-vanced HCC in a phase II study with a two-stage designand the results are disappointing because the medianTTP was 8 weeks (80). This suggests that exclusiveinhibition of the MAPK pathway is insufficient andineffective for HCC treatment (81). AZD6244 is underevaluation in HCC patients with moderate liver dysfunc-tion and normal liver function in a phase II study(NCT00604721) and in association with sorafenib in anAsian phase I/II study (NCT01029418).

Insulin growth factor 1 receptor inhibitors

Great interest has been shown in exploring IGFR inhibi-tors in HCC. Deregulation of the IGF axis and itsactivation have been involved in hepatocarcinogenesis(82, 83). Around 30% of HCCs overexpress the IGF–1R.Preclinical studies suggest that inhibition of the IGFreceptors suppresses HCC cell growth (69–84). Smallmolecules and monoclonal antibodies targeting IGF-1R(such as the monoclonal antibody A12, cixutumumaband AVE 1642) are under early clinical development. In aphase I study, we showed that AVE 1642 (Sanofi-Avantis,Paris, France) can be safely combined with active doses ofsorafenib without interaction between their respectivepharmacokinetics. Long-lasting stabilization was ob-tained in most patients because the mean time toprogression was 13.3 weeks (85).

Novel drugs targeting the Wnt-b-catenin pathway

The Wnt-b-catenin pathway plays an important role inHCC. Activation of the Wnt cascade had been shown in

about 30% of HCC and b-catenin mutations in around20% of cases (86). Although the clinical and therapeuticrelevance of the Wnt-b-catenin pathway in HCC has notbeen elucidated, drugs targeting this pathway are inthe early stages of evaluation for HCC. Effective ther-apeutic inhibition of this pathway seems to be fairlycomplex (87).

Transforming growth factor-b inhibitors

Although TGF-b inhibits hepatocyte cell growth in thenormal liver, HCC mainly occurs in injured liversincluding those with activated TGF-b signalling (88,89). Previous studies have shown that the disruption ofTGF-b signalling in mice through dominant-negativetransforming growth factor receptor 2 accelerates chemi-cally induced hepatocarcinogenesis (90). In preclinicalmodels, treatment with TGF-b induced senescence inwell-differentiated HCC cell lines with preliminary evi-dence for antitumour activity. This effect was associatedwith in vivo senescence-associated b-galactosidase activ-ity in tumour cells (91). Further investigations andclinical studies could clarify the role of TGF-b signallingas a potential target for HCC.

Conclusion

Several novel anticancer agents are currently underinvestigation for HCC. These drugs were investigatedbased on current knowledge on hepatocellular carcino-genesis, and the results have been encouraging in pre-clinical evaluations. Although none of these agents haveyet demonstrated significant clinical benefits, it is likelythat based on current trials, patients will have access tomore therapeutic options in the next few years.

Acknowledgements

This work was funded in part by AAREC (Associationd’Aide a la Recherche et l’Enseignement en Cancerologie).

Conflictsof interest

Sandrine Faivre is a consultant for Pfizer Inc. and Bayer.Eric Raymond is a consultant for Pfizer Inc., Bayerand Novartis. Mohamed Bouattour has no conflicts todeclare.

Notes: Information for this review was compiled bysearching PubMed and MEDLINE databases for articlespublished until September 2010. Only articles publishedin English were considered. The search terms usedincluded ‘hepatocellular carcinoma’ in association withthe search terms: ‘angiogenesis’, ‘VEGFR’, ‘PDGFR’, ‘su-nitinib’, ‘sorafenib’, ‘bevacizumab’, ‘thalidomide’, ‘mTORinhibitors’, ‘rapamycin’, ‘rapalogues’, ‘oxaliplatin’, ‘doxor-ubicin’, ‘PIAF’, ‘IGF1-R inhibitor’, ‘natural product’, ‘me-tastatic’, ‘clinical trial’, ‘antiangiogenic agents’, ‘brivanib’,‘targeted therapy’, ‘cytotoxic therapy’ ‘and’ ‘drug



resistance’. Full articles were obtained and references werechecked for additional material when appropriate.

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Novel molecular therapies in hepatocellular carcinoma