Liver International 2011

Liver International ISSN 1478-3223

Novel molecular therapies in hepatocellular carcinoma
Sandrine Faivre, Mohamed Bouattour and Eric Raymond
ˆ
Department of Medical Oncology, Beaujon/Bichat University Hospital, Assistance Publique-Hopitaux de Paris, University INSERM U728, Paris 7, Clichy,
France

Keywords Abstract
angiogenesis inhibitors – clinical trial – The approval of sorafenib as the standard of care (SOC) for advanced
hepatocellular carcinoma – targeted therapies hepatocellular carcinoma (HCC) fostered interest to further evaluate several
other targeted therapies and extend the positioning of sorafenib alone and in
Abbreviations combination with other drugs and local therapies at earlier stages and in an
HCC, hepatocellular carcinoma; PDGFR,
adjuvant setting. This review highlights current research using targeted
platelet-derived growth factor receptor; SOC,
therapies in HCC. Information for this review was compiled by searching
standard of care; VEGF, vascular endothelial
PubMed and MEDLINE databases for articles published until September
growth factor.
2010. Several small molecules and humanized antibodies with anti-angiogenic
Correspondence and antiproliferative properties are currently being investigated in preclinical
Eric Raymond, MD, PhD, Department of and/or clinical trials. Results are awaited from these clinical trials and offer
Medical Oncology, Beaujon/Bichat University promise for extending the current treatment options in HCC. Currently
ˆ
Hospital, Assistance Publique-Hopitaux de Paris, published data suggest that substantial progress may be achieved in the
University INSERM U728, Paris 7 Diderot, 100 treatment of patients with HCC in the next 10 years.
´ ´
boulevard du General Leclerc, 92110 Clichy,
France
Tel: 133 1 40 87 56 14
Fax: 133 1 40 87 54 87
e-mail: eric.raymond@bjn.aphp.fr

Received 10 November 2010
Accepted 26 November 2010

DOI:10.1111/j.1478-3231.2010.02395.x

Chemotherapy, including single agent doxorubicin, mul- Drug targets in hepatocellular carcinoma
tidrug regimens such as platinum–ifospahmide–adria-
mycin–5FU and more recently platinum-based doublets The carcinogenesis of HCC is heterogeneous and
such as GEMOX (gemcitabin and oxaliplatin) or FOL- complex (3). Several critical signalling pathways and
FOX (5ﬂuorouracil and oxaliplatin), has long been the molecular disturbances involved in the development of
mainstay standard of care in patients with advanced HCC and tumour invasion have been described exten-
hepatocellular carcinoma (HCC). Although activity has sively. The genetic disturbances and disrupted signalling
been suggested in a number of case reports and small pathways involved in the proliferation, survival, differ-
clinical trials, none of those regimens has demonstrated entiation, invasion and metastasis of HCC cells have been
an improvement in overall survival (OS) (1). Only one reviewed elsewhere (4–7).
recent clinical study showed that FOLFOX improved the Hepatocellular carcinoma is one of the most vascular-
OS compared with doxorubicin in Asian patients (2). ized solid cancers, associated with a high tendency
Sorafenib is the ﬁrst targeted therapy shown to improve towards vascular invasion. Immunohistochemical stu-
survival and has led to therapeutic options for HCC. dies showed that increased microvessel density was
Furthermore, improved understanding of tumour biol- associated with a poor outcome after surgery and corre-
ogy and critical signalling pathways in HCC have sug- lated with a risk of vascular invasion, metastasis and a
gested that several key kinases may be targets for novel poor prognosis (8). Vascular endothelial growth factor
anticancer agents. (VEGF) is the principal mediator of angiogenesis in HCC
The aim of this review was to discuss the use of these (9–11). Most HCC overexpress VEGF and have an
emerging drugs in HCC and, in particular, the challenges aberrant VEGF expression (9–12). High VEGF expres-
of clinical development. sion has been associated with decreased survival (9).

Liver International (2011)

c 2011 John Wiley & Sons A/S 151

Targeted therapies in HCC Faivre et al.

Research has primarily targeted pro-angiogenic growth advanced disease and in whom hepatitis B infection was
factors such as VEGF (using bevacizumab) or membrane the prevalent cause of cirrhosis. The median OS was 6.5
tyrosine kinase receptors such as vascular endothelial months in the sorafenib group versus 4.2 months in the
growth factor receptor (VEGFR) (using sorafenib, suni- placebo group (HR = 0.68; 95% CI 0.500.93; P = 0.014)
tinib, brivanib and others). Other pro-angiogenic factors (21). Tolerance to sorafenib in these two studies was
such as platelet-derived growth factor receptor (PDGFR) generally good. The most common grade 3 drug-related
and basic fibroblast growth factor receptor FGF (bFGF; adverse events in the Sorafenib HCC Assessment Rando-
FGF-2) have been shown to play crucial roles in HCC mized Protocol and Asian-Pacific studies, including
angiogenesis, making them attractive candidates for diarrhoea and hand–foot skin reaction, occurred in
targeted therapies. o 10% of patients. Noticeably, the incidence of bleeding
The epidermal growth factor receptor (EGFR) is over- was similar in the experimental and the placebo arms
expressed in 40–70% of HCC, and proliferation was (20). Based on these data, the United States (US) Food
shown to be dependent on stimulation of EGFR by and Drug Administration (FDA), European Medicine
transforming growth factor (TGF)-a or EGF in several Agency (EMA) and other regulatory authorities in the
HCC cells (13). Thus, targeting EGFR is a logical option world approved sorafenib for advanced HCC.
for the treatment of HCC. The results of preclinical
models of therapeutic approaches using neutralizing
Anti-angiogenic agents in clinical development
antibodies against EGFR (cetuximab or panitumumab)
or small-molecule EGFR tyrosine kinase inhibitors Sunitinib (SU011248, Pfizer Inc., New York, USA) –
(gefitinib, erlotinib and lapatinib) have been interesting sunitinib malate is another oral multityrosine kinase
(14, 15). targeting the VEGFR-1, -2, PDGFR-a, -b, c-Kit, Flt-3
The phosphatidylinositol 3-kinase (PI3K)/Akt/mam- and RET. Sunitinib was identified in a drug discovery
malian target of the rapamycin (mTOR) pathway was programme designed to identify more potent VEGFRs
shown to be crucial in HCC cell survival in several and PDGFRs inhibitors (23), which, as described above,
preclinical models. This pathway was responsible for play important roles in the angiogenesis of HCC. Suniti-
downstream cell signalling of various tyrosine kinase nib has already been approved for the treatment of renal
receptors, such as VEGFR, EGFR, PDGFR and IGF-1R. cell carcinoma as well as gastrointestinal stromal tu-
Genomic studies indicate that about 50% of patients mours that are refractory or intolerant to imatinib.
with HCC have mTOR signalling disturbances (16). In Recently, in a placebo-controlled randomized phase III
HCC, the activation of the PI3K/Akt/mTOR pathway is trial, this compound was shown to exert a significant
associated with a poor prognosis (17). This pathway can clinical benefit on progression-free survival (PFS) and
be targeted at various levels but at present, mTOR safety in patients with advanced pancreatic endocrine
inhibitors such as rapamycin or its analogues (ever- tumours, another hypervascularized tumour (24). In
olimus and temsirolimus) are the main available options. xenograft models of HCC, sunitinib induced tumour
growth inhibition by increasing apoptosis, reducing
microvessel density and inhibiting cell proliferation
Sorafenib: a validated proof of concept for
(25). The results of three previous independent phase II
targeted therapy
studies on the efficacy and tolerance of sunitinib in
Sorafenib (Bayer Pharmaceuticals Corporation, Leverku- patients with advanced HCC were encouraging (26–28).
sen, Germany) is an oral multityrosine kinase inhibitor In the European/Asian study, a low response rate was
targeting the intracellular serine/threonine Raf kinase, obtained despite the marked antitumour activity because
the VEGFR-2 and -3, PDGFR-b, Fms-like tyrosine kinase 35% of patients treated with 50 mg/day sunitinib
3 (Flt-3). In HCC cell lines and xenograft models, (4 weeks on/2 weeks off) achieved stable disease for over
sorafenib has been shown to prevent tumour cell growth 3 months, resulting in disease control of 37.8% (26).
and induce apoptosis as well as anti-angiogenic effects Similar results were observed with the use of sunitinib at
(18, 19). Sorafenib is the first and only drug so far shown the dose of 37.5 mg/day with the same schedule because
to improve the OS in patients with advanced HCC in two stable disease was reported in 50% of patients (27). The
large multicentre, double-blind, placebo-controlled ran- median OS was 8 and 9.8 months respectively (26, 27).
domized phase III trials (20, 21). These two large trials More recently, the results of a Swiss phase II study with a
were performed based on promising results from a phase continuous daily dose of sunitinib of 37.5 mg showed a
II study (22). In the western trial, the benefit of sorafenib PFS at 12 weeks in 33% of patients. The median OS was
in the European-American population was the result of 9.3 months (28). A multinational, phase III study
an increase in the median OS from 7.9 months in the (NCT00699374) comparing sunitinib with sorafenib in
placebo group to 10.7 months in the sorafenib group patients with advanced HCC was discontinued on 22
(HR = 0.69; 95% CI 0.55–0.87; P = 0.00058). Sorafenib April 2010, because of a higher incidence of serious
extended the OS by 44%, and decreased the relative risk adverse events in the sunitinib arm than the sorafenib
of death by 31% (20). The same increase in survival was arm, and because sunitinib did not meet the primary
confirmed in the Asian-Pacific population that had more endpoint in the overall population. The details of this

152
c 2011 John Wiley & Sons A/S

Faivre et al. Targeted therapies in HCC

trial will soon be available. The dosing and schedules of OS of 10.4 months. The benefit appears to be limited in
sunitinib seem to be complex in patients with HCC (29). patients with CP class B because the median TTP was 3.7
Frequent underlying liver disease generate a narrow months and the median OS was 2.5 months (37). Based
therapeutic index and the routine daily dose of 50 mg on these encouraging results, the efficacy and tolerance of
used in other tumour types does not seem to be suitable a daily dose of 17.5 mg linifanib is now being compared
in these patients (30). with that of sorafenib in an international randomized
Brivanib (BMS-582664; Bristol-Meyers Squibb, New non-blinded phase III study in patients CP class A and
York, USA) – brivanib alaninate is a potent, oral, selective advanced HCC (NCT01009593).
inhibitor of VEGFR-2, -3 and FGFR-2, -3, tyrosine Axitinib (AG-013736; Pfizer Inc.) – axitinib is a potent
kinases. FGFR inhibition could provide an add-on ben- inhibitor of VEGFR tyrosine kinase, PDGFR and Kit.
efit in HCC compared with VEGFR/PDGFR inhibitors. Axitinib had been shown to have potent preclinical
In derived HCC xenografts, brivanib significantly sup- activity in various models (38). Interestingly, no cross-
pressed tumour growth, resulting in decreased mean resistance has been found between axitinib and other
blood microvessel density as well as increased apoptosis agents because the antitumour activity of axitinib was
and a reduction in microvessel density (31). Similar reported in patients with metastatic RCC in whom
results were reported in a broad range of human tumour treatment with sunitinib, sorafenib and cytokines thera-
xenografts, encompassing models of chemoresistant dis- pies were unsuccessful (39). A combined phase II/III trial
ease. Assessment of angiogenesis by dynamic contrast- evaluating axitinib as a second-line agent in advanced
enhanced MRI showed a significant reduction in tumour HCC is being planned.
vascular density and in blood flow (32). Brivanib Cediranib (AZD2171, AstraZeneca, Wilmington, USA)
(800 mg daily) as either a first-line or a second-line – AZD2171, a potent oral small-molecule pan-VEGFR
therapy was evaluated in a phase II open-label study in inhibitor that blocks PDGFR and c-Kit, has been shown
patients with advanced HCC. Interim efficacy and safety to have antitumour activity in a broad range of human
results were reported at ASCO 2009 (33) and updated at tumour xenograft models. Oral daily doses of 45 mg or
ILCA 2009 (34). The median OS was 10 months in the less of AZD2171 were generally well tolerated and
first-line treated group and 9.8 months in the second-line associated with encouraging antitumour activity in a
treated group (including prior treatment with sorafenib). wide variety of advanced solid tumours (40). AZD2171
Major grade Z3 toxicities were fatigue (16%), hypona- has been tested in a two-stage phase II study in patients
traemia (15%) and hypertension (11%). Based on these with non-resectable HCC. At the dose of 45 mg/day, 84%
results and evidence of antitumour activity, brivanib is of the evaluated patients experienced grade 3 toxicities
currently being evaluated in phase II trials in patients including fatigue, hypertension and anorexia (41). Poor
with advanced HCC as a first-line treatment compared tolerance to this agent could be due in part to underlying
with sorafenib (NCT00858871) as a second-line therapy cirrhosis because liver metabolism could be impaired by
compared with placebo (NCT00825955) and also com- liver dysfunction. Thus, another phase II study was
pared with placebo as an adjuvant therapy to transarter- planned with a reduced dose of AZD2171. However, this
ial chemo-embolization (NCT00908752). study has been suspended (NTC00427973).
Linifanib (ABT-869, Abbott, Abbott Park, USA) – TSU-68 (SU6668, Taiho Pharmaceutical Co. Ltd,
linifanib is a novel, orally bioavailable, small-molecule Tokyo, Japan) – TSU-68 is an oral multikinase inhibitor
receptor tyrosine kinase inhibitor that targets VEGF and of VEGFR-2, PDGFR and FGFR. This compound has
PDGF receptor families. In a phase I study, linifanib was been assessed in 35 Japanese patients with CP classes A/B
found to be well tolerated at doses 0.25 mg/kg daily. HCC in a coupled phase I/II study (42). Two hundred
After 17 months in the cohort of 33 patients with HCC, milligrams of STU-68 was administered twice a day. In
prolonged stable disease was achieved in two patients this study, 11.4% of patients experienced grade 3/4
with HCC. Dynamic radiological assessment showed adverse events including elevated AST/ALT levels and
reduced vascular permeability of the tumour and vascu- thrombocytopenia. An objective response was observed
larity correlated to drug exposure (35). Recently, interim in 9.6% of patients (complete response: 2.9% and partial
results of an open-label multicentre phase II trial of ABT- response: 5.7%). Stable disease was achieved in 42.8% of
869 in patients with advanced HCC were reported (34). patients. The median PFS was 2.1 months compared with
ABT-869 was administered at 0.25 mg/kg daily to Child- a surprising median OS of 13.1 months (42).
Pugh (CP) class A patients or every other day in CP class Pazopanib (GW786034, GlaxoSmithKline, Brentford,
B patients. Thirty-four patients could be evaluated in this UK) – pazopanib is an oral, multitargeted tyrosine kinase
cohort, and an objective response was achieved in 8.7% inhibitor that targets VEGFRs, PDGFR and c-Kit. This
of CP class A patients but in none of the CP class B compound recently obtained US FDA approval for the
patients. The median TTP was 112 days and the median treatment of advanced renal cell carcinoma. Pazopanib
OS was 295 days. The most common grade Z3 toxicities was evaluated in a phase I study in patients with
were hypertension (20.6%) and fatigue (11.8%). Up- advanced HCC (43). The maximum tolerated dose
dated results showed a clinical benefit in CP class A was established as 600 mg twice a day. The main grade
patients with a median TTP of 5.4 months and a median 3/4-related side effects were diarrhoea (4%) and


c 2011 John Wiley Sons A/S 153


hypertension (26%). Partial response and stable disease isoforms, has emerged as an important therapeutic agent.
were observed in 7.5 and 41% of patients respectively. It has been approved for the treatment of several carci-
Thus, pazopanib appears to be a promising active drug nomas including colorectal, non-small-cell lung, breast
for further clinical development in HCC. cancer and metastatic renal cell carcinoma. In preclinical
Vandetanib (ZD6474, AstraZeneca, Wilmington, models of HCC, bevacizumab induced a significant
USA) – ZD6474 is an orally active inhibitor of VEGFR, decrease in vessel density and prolonged time to progres-
EGFR and RET tyrosine kinases. In preclinical models sion of tumour-bearing mice (53). Bevacizumab was
and under experimental conditions, ZD6474 was shown evaluated as a single agent for the treatment of advanced
to inhibit HCC cell proliferation adhesion, migration HCC in two phase II trials. In the first study in 46
and invasion (44). ZD6474 is currently being evaluated patients with locally advanced HCC, partial responses
in a phase II trial in patients with advanced HCC were observed in 13% and disease stabilization for at least
(NCT00508001). 6 months was obtained in 65% of patients, with a median
Vatalanib (PTK787/ZK, Novartis, Basel, Switzerland PFS of 6.9 months (54). The OS rate at 1, 2 and 3 years
and Bayer Schering Pharma) – PTK787 is an orally active, was 53, 28 and 23% respectively. Comparable results were
selective inhibitor of all VEGFR tyrosine kinases. At reported in the interim results of a French study, because
higher concentrations, this compound also inhibits other partial response and stable disease for at least 16 weeks
tyrosine kinases such as PDGFR and Kit. PTK787 in- were observed in 12.5 and 29 % respectively (55).
duced tumour cell apoptosis and reduced vessel forma- Updated data presented at ASCO 2009 showed that
tion. Its effect was enhanced by the induction of hypoxia bevacizumab induced 16% partial response and 47%
through ligation of the hepatic artery (45), which sug- stable disease in 38 patients (56). Despite these promising
gests that this compound might be interesting in combi- results, it should be noted that patients with a CLIP score
nation with transarterial chemoembolization. In the 4 3 (55), liver involvement of the tumour of 4 50%
phase I study, the maximum tolerated dose was 750 mg and/or with vascular invasion and/or extrahepatic spread
daily and stable disease was observed in 50% of patients disease (54) were excluded from trials. Therefore, it is
(46). For pharmacological and marketing reasons, the difficult to compare these results with those obtained
development of PTK787/ZK was not pursued in HCC. with sorafenib and probably only well-selected patients
BIBF 1120 (Vargatef, Boehringer Ingelheim, Ridge- can benefit from this therapy. Moreover, these results
field, Germany) – BIBF 1120 is an oral triple angiokinase were accompanied by a high incidence of adverse drug-
inhibitor targeting VEGF, FGFR and PDGF receptors related events, in particular, severe bleeding, which
that showed antitumour activity in preclinical models occurred in 11% of patients in the American study (54)
(47). Its activity on FGFR was considered to be a and required withdrawal of the drug in 20% of patients in
potential advantage to broaden its activity over other the French study (55). Other serious side effects included
VEGFR inhibitors. This compound is being compared arterial thrombosis (6%) and hypertension (15%).
with sorafenib in two different phase II studies to The combination of bevacizumab with cytotoxic agents
evaluate the safety and the efficacy for advanced HCC in was also evaluated in phase II studies and was shown to be
European patients (NCT01004003) and Asian patients reasonably safe, with a moderate clinical benefit (57–59).
(NCT00987935). The combination of bevacizumab and GEMOX was eval-
Foretinib (GSK1363089, EXEL-2880; XL-880, Exelixis, uated in a phase II study. Twenty per cent of the 33 patients
San Francisco, USA) – foretinib is an orally bioavailable enrolled showed an objective response. The median OS was
selective inhibitor of c-Met and VEGFR-2 tyrosine ki- 9.6 months (57). Adding bevacizumab did not markedly
nases. Targeting the c-Met pathway could be a potential improve the clinical benefit because results with GEMOX
therapy in HCC because dysregulation of c-MET as well alone were similar in a phase II study, with a response rate
as its ligand HGF are frequent (48) and overexpression of of 18% and a median OS of 11.5 months (60).
c-Met correlates with more advanced HCC (49). The
exact role of this pathway in the pathogenesis of HCC has
Anti-epidermal growth factor receptor under
not been clearly elucidated. Blocking the HGF/c-MET
clinical development
pathway during the orthotopic transplant of HCC mod-
els induced growth suppression and a decrease in angio- Cetuximab (C225, ImClone Systems, New York, USA
genesis (50). Foretinib was found to be potentially active and Merck Serono, Darmstadt, Germany), a chimeric
in preclinical HCC models with inhibition of tumour monoclonal antibody directed against EGFR, is already
angiogenesis, tumour cell proliferation and metastasis part of standard therapy in patients with metastatic
(51). Although several molecules targeting MET path- colorectal cancer and head neck cancer. Cetuximab was
ways are under development (52), only foretinib is being evaluated as a single agent in two phase II studies (61,
investigated for safety and tolerance in patients with 62). In the first study, no clinical responses were observed
advanced HCC in a phase I/II study (NCT00920192). and stable disease was achieved in 17% of patients. The
Bevacizumab (Genentech Inc., San Francisco, USA median OS was 9.6 months and the median PFS was 1.4
and Roche, Basel, Switzerland), a recombinant, huma- months (61). In the second open-label study, stable
nized monoclonal antibody directed against all VEGF disease was observed for at least 8 weeks in 44.4% of the

154
c 2011 John Wiley Sons A/S


cases and the median PFS was 1.8 months (62). The pathways could be developed by the tumour to bypass
results of these two studies are inconsistent; hence, the the EGF signal for its survival and cell proliferation (67,
role and activity of this compound in HCC must still be 68). A possible solution to avoid this resistance mechan-
clarified. Currently, anti-EGFR-based approaches are ism is to combine IGF-1R inhibitors and EGFR blockers
being tested in clinical trials (NCT00142428), especially and enhance the antitumour activity of the respective
in combination with conventional chemotherapy monotherapies (69, 70).
(NCT00483405). Lapatinib (GW572016, GlaxoSmithKline) is a selective
Erlotinib (OSI-774, Genentech Inc. and Roche) is a dual inhibitor of both EGFR and Human EGFR type 2
potent oral and specific inhibitor of the EGFR/HER1- (HER-2/NEU) signalling pathways. Although HER-2/
related tyrosine kinase domain. Erlotinib is already ap- NEU overexpression is rare in HCC, this compound has
proved for the treatment of metastatic or locally advanced also been evaluated in advanced HCC. Twenty-six patients
non-small-cell lung cancer and pancreatic cancer. The with advanced HCC were treated with daily lapatinib
safety and efficacy of erlotinib as a single agent in Child- orally at a dose of 1500 mg in a phase II study (71). No
Pugh class A and B patients with advanced HCC were objective responses were obtained. Approximately 40% of
reported in two phase II clinical studies. The first report patients achieved their best response. The median PFS and
showed that 32% of patients were progression-free at 6 OS were 1.9 and 12.6 months respectively. Only three
months, with disease control in 59% of cases. The median patients experienced grade 3 drug-related toxicities in-
OS for this cohort was 13 months (63). The most frequent cluding diarrhoea, rash and acute renal failure. Interest-
grade 3/4 toxicities were skin rash, diarrhoea and fatigue. ingly, patients who developed a rash (an effect of EGFR/
Treatment was significantly less well tolerated in CP class B HER1 inhibition) had a more favourable outcome with
patients (63). These results are limited by the fact that 42% longer survival compared with the overall study popula-
of enrolled patients had no underlying liver disease. In the tion (71). In another phase II study, a cohort of 40 patients
second study, erlotinib was evaluated in 40 patients with CP with advanced HCC was treated with lapatinib. Moderate
class A or B cirrhosis and advanced HCC. There was no antitumoral activity was observed because an objective
partial or complete response to erlotinib. However, the PFS response was observed in 5% of patients. The median PFS
at 4 months was 43%, and the median OS was 10.75 was 2.3 and the median OS was 6.2 months (72).
months. No correlation was found in this trial between
EGFR expression and OS (64). A phase III clinical trial is
mTOR inhibitors
ongoing to evaluate the benefit of combining erlotinib with
sorafenib compared with sorafenib plus placebo as a first- Rapamycin (sirolimus) is an mTOR kinase inhibitor with
line therapy in patients with advanced HCC antiproliferative (by inhibiting tumour cell growth and
(NCT00901901). The results of a phase II study combining proliferation) and anti-angiogenesis activities (by both
bevacizumab and erlotinib were interesting, with a median direct effects on vascular cell proliferation and indirect
time to progression of 9 months and a median OS of 15.65 effects on growth factor production). Rapamycin also
months. Major side effects included fatigue (20%), hyper- inhibits VEGF secretion and signal transduction induced
tension (15%) and gastrointestinal bleeding (12.5%) (65). by VEGF in endothelial cells ultimately altering tumour
Patients included in this study had slightly less advanced growth by an anti-angiogenic mechanism. Even if the
disease than the populations in other published phase II PI3K/AKT/mTOR pathway could be inhibited at various
trials in this setting. Further studies are needed to confirm levels, the most promising target in this pathway is
the potential synergistic activity of this combination. This mTOR. Rapamycin and its derivatives such as everolimus
combination is being compared with sorafenib as a first- (RAD001, Novartis) yielded interesting antitumour ac-
line therapy in a phase 2 study (NCT00881751) as well as a tivity in preclinical studies and xenograft models of HCC
second-line therapy (NCT01180959). (73, 74). Two small pilot studies showed promising
Gefitinib (ZD1839, AstraZeneca), another EGFR tyr- results on the efficacy of sirolimus in HCC patients with
osine kinase inhibitor, was also evaluated in a two-stage a safe profile (75, 76). The efficacy of sirolimus was
design, single-arm phase 2 study in patients with HCC evaluated in a single-arm study in 21 advanced HCC
(66). Thirty-one patients were recruited in the first stage. patients (75). Sirolimus induced a partial response and
Gefitinib induced an objective response of 3% and tumour stabilization for at least 3 months in 5 and 24%
disease stabilization of 22.6%. The median PFS was 2.8 of patients respectively. The median OS was 6.5 months.
months and the median OS was 6.5 months. Because the No major sirolimus-related side effects were observed in
criterion for the second stage of the study was not met, this study (75). In the French pilot study, 14 patients
the authors hypothesized that gefitinib was not active as a were treated with 30 mg oral sirolimus once a week (76).
single agent in patients with advanced HCC (66). A complete or a partial response according to the
These results could be explained by the possible cross- RECIST criteria was observed in 7 and 33% of patients
talk between insulin-like growth factor 1 receptor respectively. Sirolimus also seemed to be safe because no
(IGF-1R) and EGF signalling pathways (67). Gefitinib grade 4 toxicity was observed and only two patients
resistance may be associated with alternative activation of experienced grade 3 mucositis. Sirolimus did not affect
the IGF-2/IGF-1R survival pathway. Substitution liver function (76). Several phase I and phase II studies




are currently testing mTOR inhibitors as single agents about 30% of HCC and b-catenin mutations in around
(NCT00390195 and NCT00516165), in combination 20% of cases (86). Although the clinical and therapeutic
with sorafenib (NCT01008917) or with bevacizumab relevance of the Wnt-b-catenin pathway in HCC has not
(NTC00775073). Based on the safety profile in patients been elucidated, drugs targeting this pathway are in
with cirrhosis temsirolimus (CCI-779, Pfizer Inc.) is also the early stages of evaluation for HCC. Effective ther-
being evaluated in a phase II study in CP class B patients apeutic inhibition of this pathway seems to be fairly
with advanced HCC (NCT01079767). Everolimus is complex (87).
being evaluated in patients with advanced HCC with
progressive disease or as a second-line therapy in a phase Transforming growth factor-b inhibitors
III study compared with placebo either following sorafe-
nib or in patients who cannot tolerate sorafenib. Although TGF-b inhibits hepatocyte cell growth in the
normal liver, HCC mainly occurs in injured livers
including those with activated TGF-b signalling (88,
MEK/ERK inhibitors 89). Previous studies have shown that the disruption of
The Raf/MEK/ERK pathway appears to be one of the TGF-b signalling in mice through dominant-negative
most significant cellular signalling sequences in the transforming growth factor receptor 2 accelerates chemi-
development and maintenance of HCC (77). AZD6244 cally induced hepatocarcinogenesis (90). In preclinical
(ARRY-142886, AstraZeneca) is an oral, new MEK in- models, treatment with TGF-b induced senescence in
hibitor. This compound combined with rapamycin had well-differentiated HCC cell lines with preliminary evi-
been shown to have antitumour and anti-angiogenic dence for antitumour activity. This effect was associated
effects in preclinical models of human HCC (78). with in vivo senescence-associated b-galactosidase activ-
Furthermore, pharmacological inhibition of the MEK/ ity in tumour cells (91). Further investigations and
ERK pathway by the MEK inhibitor AZD6244 enhanced clinical studies could clarify the role of TGF-b signalling
the antitumour effect of sorafenib in both orthotopic and as a potential target for HCC.
ectopic models of HCC (79). However, AZD6244 as a
single agent did not show any clinical benefit. Indeed, Conclusion
this compound was evaluated in 19 patients with ad-
vanced HCC in a phase II study with a two-stage design Several novel anticancer agents are currently under
and the results are disappointing because the median investigation for HCC. These drugs were investigated
TTP was 8 weeks (80). This suggests that exclusive based on current knowledge on hepatocellular carcino-
inhibition of the MAPK pathway is insufficient and genesis, and the results have been encouraging in pre-
ineffective for HCC treatment (81). AZD6244 is under clinical evaluations. Although none of these agents have
evaluation in HCC patients with moderate liver dysfunc- yet demonstrated significant clinical benefits, it is likely
tion and normal liver function in a phase II study that based on current trials, patients will have access to
(NCT00604721) and in association with sorafenib in an more therapeutic options in the next few years.
Asian phase I/II study (NCT01029418).
Acknowledgements
Insulin growth factor 1 receptor inhibitors
This work was funded in part by AAREC (Association
Great interest has been shown in exploring IGFR inhibi- `
d’Aide a la Recherche et l’Enseignement en Cancerologie).
tors in HCC. Deregulation of the IGF axis and its
activation have been involved in hepatocarcinogenesis Conflicts of interest
(82, 83). Around 30% of HCCs overexpress the IGF–1R.
Preclinical studies suggest that inhibition of the IGF Sandrine Faivre is a consultant for Pfizer Inc. and Bayer.
receptors suppresses HCC cell growth (69–84). Small Eric Raymond is a consultant for Pfizer Inc., Bayer
molecules and monoclonal antibodies targeting IGF-1R and Novartis. Mohamed Bouattour has no conflicts to
(such as the monoclonal antibody A12, cixutumumab declare.
and AVE 1642) are under early clinical development. In a
phase I study, we showed that AVE 1642 (Sanofi-Avantis, Notes: Information for this review was compiled by
Paris, France) can be safely combined with active doses of searching PubMed and MEDLINE databases for articles
sorafenib without interaction between their respective published until September 2010. Only articles published
pharmacokinetics. Long-lasting stabilization was ob- in English were considered. The search terms used
tained in most patients because the mean time to included ‘hepatocellular carcinoma’ in association with
progression was 13.3 weeks (85). the search terms: ‘angiogenesis’, ‘VEGFR’, ‘PDGFR’, ‘su-
nitinib’, ‘sorafenib’, ‘bevacizumab’, ‘thalidomide’, ‘mTOR
inhibitors’, ‘rapamycin’, ‘rapalogues’, ‘oxaliplatin’, ‘doxor-
Novel drugs targeting the Wnt-b-catenin pathway
ubicin’, ‘PIAF’, ‘IGF1-R inhibitor’, ‘natural product’, ‘me-
The Wnt-b-catenin pathway plays an important role in tastatic’, ‘clinical trial’, ‘antiangiogenic agents’, ‘brivanib’,
HCC. Activation of the Wnt cascade had been shown in ‘targeted therapy’, ‘cytotoxic therapy’ ‘and’ ‘drug

156


resistance’. Full articles were obtained and references were 16. Villanueva A, Chiang DY, Newell P, et al. Pivotal role of
checked for additional material when appropriate. mTOR signaling in hepatocellular carcinoma. Gastroenter-
ology 2008; 135: 1972–83.
17. Schmitz KJ, Wohlschlaeger J, Lang H, et al. Activation
of the ERK and AKT signalling pathway predicts poor
References prognosis in hepatocellular carcinoma and ERK activation
1. Mathurin P, Rixe O, Carbonell N, et al. Overview of in cancer tissue is associated with hepatitis C virus
medical treatments in unresectable hepatocellular carcino- infection. J Hepatol 2008; 48: 83–90.
ma – an impossible meta-analysis? Aliment Pharmacol Ther 18. Huynh H, Ngo VC, Koong HN, et al. Sorafenib and
1998; 12: 111–26. rapamycin induce growth suppression in mouse models of
2. Qin S, Bai Y, Ye S, et al. Phase III study of oxaliplatin plus 5- hepatocellular carcinoma. J Cell Mol Med 2009; 13:
fluorouracil/leucovorin (FOLFOX4) versus doxorubicin as 2673–83.
palliative systemic chemotherapy in advanced HCC in 19. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/
Asian patients. J Clin Oncol 2010; 28: 15S (abstract 4008). ERK pathway, inhibits tumor angiogenesis, and induces
3. Farazi PA, DePinho RA. Hepatocellular carcinoma patho- tumor cell apoptosis in hepatocellular carcinoma model
genesis: from genes to environment. Nat Rev Cancer 2006; PLC/PRF/5. Cancer Res 2006; 66: 11851–8.
6: 674–87. 20. Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib in advanced
4. Thomas MB, Abbruzzese JL. Opportunities for targeted hepatocellular carcinoma. N Engl J Med 2008; 359:
therapies in hepatocellular carcinoma. J Clin Oncol 2005; 378–90.
21. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of
23: 8093–108.
sorafenib in patients in the Asia-Pacific region with ad-
5. Hoshida Y, Toffanin S, Lachenmayer A, et al. Molecular
vanced hepatocellular carcinoma: a phase III randomised,
classification and novel targets in hepatocellular carcinoma:
double-blind, placebo-controlled trial. Lancet Oncol 2009;
recent advancements. Semin Liver Dis 2010; 30: 35–51.
10: 25–34.
6. Llovet JM, Bruix J. Molecular targeted therapies in hepato-
22. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of
cellular carcinoma. Hepatology 2008; 48: 1312–27.
sorafenib in patients with advanced hepatocellular carcino-
7. Pang RW, Poon RT. From molecular biology to targeted
ma. J Clin Oncol 2006; 24: 4293–300.
therapies for hepatocellular carcinoma: the future is now.
23. Faivre S, Demetri G, Sargent W, Raymond E. Molecular
Oncology 2007; 72(Suppl. 1): 30–44.
basis for sunitinib efficacy and future clinical development.
8. Poon RT, Ng IO, Lau C, et al. Tumor microvessel density as a
Nat Rev Drug Discov 2007; 6: 734–45.
predictor of recurrence after resection of hepatocellular carci-
24. Niccoli P, Raoul J, Bang Y, et al. Updated safety and efficacy
noma: a prospective study. J Clin Oncol 2002; 20: 1775–8.
results of the phase III trial of sunitinib (SU) versus
9. Poon RT, Ho JW, Tong CS, et al. Prognostic significance of
placebo (PBO) for treatment of pancreatic neuroendocrine
serum vascular endothelial growth factor and endostatin in tumors (NET). ASCO Annual Meeting Proceedings (Post-
patients with hepatocellular carcinoma. Br J Surg 2004; 91: Meeting Edition). J Clin Oncol 2010; 28: 15S (abstract
1354–60. 4000).
10. Yoshiji H, Kuriyama S, Yoshii J, et al. Vascular endothelial 25. Huynh H, Ngo VC, Choo SP, et al. Sunitinib (SUTENT,
growth factor tightly regulates in vivo development of SU11248) suppresses tumor growth and induces apoptosis
murine hepatocellular carcinoma cells. Hepatology 1998; in xenograft models of human hepatocellular carcinoma.
28: 1489–96. Curr Cancer Drug Targets 2009; 9: 738–47.
11. Moon WS, Rhyu KH, Kang MJ, et al. Overexpression of 26. Faivre S, Raymond E, Boucher E, et al. Safety and efficacy of
VEGF and angiopoietin 2: a key to high vascularity of sunitinib in patients with advanced hepatocellular carcino-
hepatocellular carcinoma? Mod Pathol 2003; 16: 552–7. ma: an open-label, multicentre, phase II study. Lancet Oncol
12. Chow NH, Hsu PI, Lin XZ, et al. Expression of vascular 2009; 10: 794–800.
endothelial growth factor in normal liver and hepatocellu- 27. Zhu AX, Sahani DV, Duda DG, et al. Efficacy, safety, and
lar carcinoma: an immunohistochemical study. Hum potential biomarkers of sunitinib monotherapy in ad-
Pathol 1997; 28: 698–703. vanced hepatocellular carcinoma: a phase II study. J Clin
13. Harada K, Shiota G, Kawasaki H. Transforming growth Oncol 2009; 27: 3027–35.
factor-alpha and epidermal growth factor receptor in 28. Koeberle D, Montemurro M, Samaras P, et al. Continuous
chronic liver disease and hepatocellular carcinoma. Liver sunitinib treatment in patients with advanced hepatocellu-
1999; 19: 318–25. lar carcinoma: a Swiss Group for Clinical Cancer Research
14. Huether A, Hopfner M, Baradari V, Schuppan D, Scher¨ bl u (SAKK) and Swiss Association for the Study of the Liver
H. EGFR blockade by cetuximab alone or as combination (SASL) multicenter phase II trial (SAKK77/06). Oncologist
therapy for growth control of hepatocellular cancer. Bio- 2010; 15: 285–92.
chem Pharmacol 2005; 70: 1568–78. 29. Faivre S, Bouattour M, Dreyer C, Raymond E. Sunitinib in
15. Hopfner M, Sutter AP, Huether A, et al. Targeting the hepatocellular carcinoma: redefining appropriate dosing,
epidermal growth factor receptor by gefitinib for treatment schedule, and activity endpoints. J Clin Oncol 2009; 27:
of hepatocellular carcinoma. J Hepatol 2004; 41: 1008–16. 248–50.




30. Sablin MP, Dreyer C, Colichi C, et al. Benefits from 43. Yau CC, Chen PJ, Curtis CM, et al. A phase I study of
pharmacological and pharmacokinetic properties of suni- pazopanib in patients with advanced hepatocellular carci-
tinib for clinical development. Expert Opin Drug Metab noma. ASCO Annual Meeting Proceedings (Post-Meeting
Toxicol 2010; 6: 1005–15. Edition). J Clin Oncol 2009; 27: 15S (abstract 3561).
31. Huynh H, Ngo VC, Fargnoli J, et al. Brivanib alaninate, a 44. Giannelli G, Azzariti A, Sgarra C, et al. ZD6474 inhibits
dual inhibitor of vascular endothelial growth factor recep- proliferation and invasion of human hepatocellular carci-
tor and fibroblast growth factor receptor tyrosine kinases, noma cells. Biochem Pharmacol 2006; 71: 479–85.
induces growth inhibition in mouse models of human 45. Yang ZF, Poon RT, Liu Y, et al. High doses of tyrosine kinase
hepatocellular carcinoma. Clin Cancer Res 2008; 14: inhibitor PTK787 enhance the efficacy of ischemic hypoxia
6146–53. for the treatment of hepatocellular carcinoma: dual effects
32. Bhide RS, Lombardo LJ, Hunt JT, et al. The antiangiogenic on cancer cell and angiogenesis. Mol Cancer Ther 2006; 5:
activity in xenograft models of brivanib, a dual inhibitor of 2261–70.
vascular endothelial growth factor receptor-2 and fibroblast 46. Koch I, Baron A, Roberts S, et al. Influence of hepatic
growth factor receptor-1 kinases. Mol Cancer Ther 2010; 9: dysfunction on safety, tolerability, and pharmacokinetics
369–78. (PK) of PTK787/ZK 222584 in patients (Pts) with unre-
33. Raoul JL, Finn RS, Kang YK, et al. An open-label phase II sectable hepatocellular carcinoma (HCC). J Clin Oncol
study of first- and second-line treatment with brivanib in 2005; 23(Suppl. 16): 4134a.
patients with hepatocellular carcinoma (HCC). Proceed- 47. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple
ings of the 2009 ASCO annual meeting. J Clin Oncol 2009; angiokinase inhibitor with sustained receptor blockade and
27: 15S (abstract 4577). good antitumor efficacy. Cancer Res 2008; 68: 4774–82.
34. Raoul JL, Finn RS, Kang YK, et al. Phase 2 study of first- 48. Takami T, Kaposi-Novak P, Uchida K, et al. Loss of
and second-line treatment with brivanib in patients with hepatocyte growth factor/c-Met signaling pathway acceler-
hepatocellular carcinoma (HCC). Presented in ILCA, Milan, ates early stages of N-nitrosodiethylamine induced hepato-
2009 (abstract 30). carcinogenesis. Cancer Res 2007; 67: 9844–51.
35. Wong CI, Koh TS, Soo R, et al. Phase I and biomarker study 49. Osada S, Kanematsu M, Imai H, Goshima S. Clinical
of ABT-869, a multiple receptor tyrosine kinase inhibitor, significance of serum HGF and c-Met expression in tumor
in patients with refractory solid malignancies. J Clin Oncol tissue for evaluation of properties and treatment of hepa-
2009; 27: 4718–26. tocellular carcinoma. Hepatogastroenterology 2008; 55:
36. Toh H, Chen P, Carr BI, et al. A phase II study of ABT-869 544–9.
in hepatocellular carcinoma (HCC): interim analysis. In 50. Son G, Hirano T, Seki E, et al. Blockage of HGF/c-Met
ASCO (Chicago, 2009). ASCO Annual Meeting Proceed- system by gene therapy (adenovirus-mediated NK4 gene)
ings (Post-Meeting Edition). J Clin Oncol 2009; 27: 15S suppresses hepatocellular carcinoma in mice. J Hepatol
(abstract 4581). 2006; 45: 688–95.
37. Toh H, Chen P, Carr BI, et al. Linifanib phase II trial in 51. Qian F, Engst S, Yamaguchi K, et al. Inhibition of tumor cell
patients with advanced hepatocellular carcinoma (HCC). growth, invasion, and metastasis by EXEL-2880 (XL880,
Presented at the ASCO GI 2010. J Clin Oncol 2010; GSK1363089), a novel inhibitor of HGF and VEGF receptor
28(Suppl. 15): 15S (abstract 4038). tyrosine kinases. Cancer Res 2009; 69: 8009–16.
38. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical 52. Comoglio PM, Giordano S, Trusolino L. Drug develop-
antiangiogenesis and antitumor activities of axitinib (AG- ment of MET inhibitors: targeting oncogene addiction and
013736), an oral, potent, and selective inhibitor of vascular expedience. Nat Rev Drug Discov 2008; 7: 504–16.
endothelial growth factor receptor tyrosine kinases 1, 2, 3. 53. Finn RS, Bentley G, Britten CD, Amado R, Busuttil RW.
Clin Cancer Res 2008; 14: 7272–83. Targeting vascular endothelial growth factor with the
39. Rini BI, Wilding G, Hudes G, et al. Phase II study of monoclonal antibody bevacizumab inhibits human hepa-
axitinib in sorafenib-refractory metastatic renal cell carci- tocellular carcinoma cells growing in an orthotopic mouse
noma. J Clin Oncol 2009; 27: 4462–8. model. Liver Int 2009; 29: 284–90.
40. Drevs J, Siegert P, Medinger M, et al. Phase I clinical study 54. Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating
of AZD2171, an oral vascular endothelial growth factor the clinical and biologic effects of bevacizumab in unre-
signaling inhibitor, in patients with advanced solid tumors. sectable hepatocellular carcinoma. J Clin Oncol 2008; 26:
J Clin Oncol 2007; 25: 3045–54. 2992–8.
41. Alberts SR, Morlan BW, Kim GP, et al NCCTG phase II trial 55. Malka D, Dromain C, Farace F, et al. Bevacizumab in
(N044J) of AZD2171 for patients with hepatocellular patients with advanced hepatocellular carcinoma (HCC):
carcinoma (HCC) – interim review of toxicity. 2007 preliminary results of a phase II study with circulating
Gastrointestinal Cancer Symposium, Orlando, 186a. endothelial cell (CEC) monitoring. J Clin Oncol 2007;
42. Kanai F, Yoshida H, Tateishi R, et al. A phase I/II trial of the 25(Suppl. 18): 4570a.
oral antiangiogenic agent TSU-68 in patients with ad- 56. Boige V, Baey C, Dromain C, et al. Circulating endothelial
vanced hepatocellular carcinoma. Cancer Chemother Phar- cells (CEC) and angiogenic proteins monitoring in patients
macol 2010 (epub ahead of print). (pts) with advanced hepatocellular carcinoma (HCC)

158


treated with bevacizumab. In Proceedings of the 2009 lapatinib in patients with advanced hepatocellular carcino-
ASCO annual meeting. J Clin Oncol 27: 15S (abstract 4597). mas. Clin Cancer Res 2009; 15: 5895–901.
57. Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of 72. Ramanathan RK, Belani CP, Singh DA, et al. A phase II
gemcitabine and oxaliplatin in combination with bevacizu- study of lapatinib in patients with advanced biliary tree and
mab in patients with advanced hepatocellular carcinoma. hepatocellular cancer. Cancer Chemother Pharmacol 2009;
J Clin Oncol 2006; 24: 1898–903. 64: 777–83.
58. Sun W, Haller DG, Mykulowycz K, et al. Combination of 73. Semela D, Piguet AC, Kolev M, et al. Vascular remodelling
capecitabine and oxaliplatin with bevacizumab in treat- and antitumoral effects of mTOR inhibition in a rat
ment of advanced hepatocellular carcinoma: a phase II model of hepatocellular carcinoma. J Hepatol 2007; 46:
study. J Clin Oncol 2007; 25(Suppl. 18): 4574a. 840–8.
59. Hsu C, Yang T, Hsu C, et al. Phase II study of bevacizumab 74. Huynh H, Chow P, Soo KC, et al. RAD001 (Everolimus)
plus capecitabine in patients with advanced/metastatic inhibits tumor growth in xenograft models of human
hepatocellular carcinoma: final report. J Clin Oncol 2008; hepatocellular carcinoma. J Cell Mol Med 2009; 13:
26(Suppl. 15): 4603a. 1371–80.
60. Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus 75. Rizell M, Anderson M, Cahlin C, et al. Effects of the
oxaliplatin (GEMOX) in patients with advanced hepatocel- mTOR inhibitor sirolimus in patients with hepatocellular
lular carcinoma (HCC): results of a phase II study. Cancer and cholangiocellular cancer. Int J Clin Oncol 2008; 13:
2007; 109: 1384–90. 66–70.
61. Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of 76. Decaens T, Luciani A, Itti E, et al. Pilot study of sirolimus in
cetuximab in patients with advanced hepatocellular carci- cirrhotic patients with advanced hepatocellular carcinoma.
noma. Cancer 2007; 110: 581–9. J Hepatol 2008; (Suppl. 13): 48a.
62. Gruenwald V, Wilkens L, Gebel M, et al. A phase II open- 77. Hynes NE, Lane HA. ERBB receptors and cancer: the
label study of cetuximab in unresectable hepatocellular complexity of targeted inhibitors. Nat Rev Cancer 2005; 5:
carcinoma – final results. J Clin Oncol 2007; 25: 18S (4598). 341–54.
63. Philip PA, Mahoney MR, Allmer C, et al. Phase II study of 78. Huynh H. AZD6244 (ARRY-142886) enhances the antitu-
erlotinib (OSI-774) in patients with advanced hepatocellu-
mor activity of rapamycin in mouse models of human
lar cancer. J Clin Oncol 2005; 23: 6657–63.
hepatocellular carcinoma. Cancer 2010; 116: 1315–25.
64. Thomas MB, Chadha R, Glover K, et al. Phase 2 study of
79. Huynh H, Ngo VC, Koong HN, et al. AZD6244 enhances
erlotinib in patients with unresectable hepatocellular carci-
the anti-tumor activity of sorafenib in ectopic and ortho-
noma. Cancer 2007; 110: 1059–67.
topic models of human hepatocellular carcinoma (HCC).
65. Thomas MB, Morris JS, Chadha R, et al. Phase II trial of the
J Hepatol 2010; 52: 79–87.
combination of bevacizumab and erlotinib in patients who
80. O’Neil BH, Williams-Goff LW, Kauh J, et al. A phase II
have advanced hepatocellular carcinoma. J Clin Oncol 2009;
study of AZD6244 in advanced or metastatic hepatocellular
27: 843–50.
carcinoma. ASCO Annual Meeting Proceedings (Post-
66. O’Dwyer PJ, Giantonio BJ, Levy DE, et al. Gefitinib in
advanced unresectable hepatocellular carcinoma: results Meeting Edition). J Clin Oncol 2009; 27: 15S (abstract
from the Eastern Cooperative Oncology Group’s Study 15574).
E1203 (Meeting Abstracts). J Clin Oncol 2006; 24: 18S 81. Shen YC, Hsu C, Cheng AL. Molecular targeted therapy for
(abstract 4143). advanced hepatocellular carcinoma: current status and
67. Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoel MJ, ¨ future perspectives. Gastroenterology 2010; 45: 794–807.
et al. Impact of IGF-1R/EGFR cross-talks on hepatoma cell 82. Scharf JG, Braulke T. The role of the IGF axis in hepato-
sensitivity to gefitinib. Int J Cancer 2006; 119: 2557–66. carcinogenesis. Horm Metab Res 2003; 35: 685–93.
68. Wheeler DL, Dunn EF, Harari PM. Understanding resis- 83. Tovar V, Alsinet C, Villanueva A, et al. IGF activation in a
tance to EGFR inhibitors-impact on future treatment molecular subclass of hepatocellular carcinoma and pre-
strategies. Nat Rev Clin Oncol 2010; 7: 493–507. clinical efficacy of IGF-1R blockage. J Hepatol 2010; 52:
69. Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoel MJ, 550–9.
et al. Insulin-like growth factor-1 receptor inhibition 84. Cantarini MC, de la Monte SM, Pang M, et al. Aspartyl–
induces a resistance mechanism via the epidermal growth asparagyl beta hydroxylase over-expression in human
factor receptor/HER3/AKT signaling pathway: rational ba- hepatoma is linked to activation of insulin-like growth
sis for cotargeting insulin-like growth factor-1 receptor and factor and notch signaling mechanisms. Hepatology 2006;
epidermal growth factor receptorin hepatocellular carcino- 44: 446–57.
ma. Clin Cancer Res 2009; 15: 5445–56. 85. Faivre S, Fartoux L, Bumsel F, et al. Phase I safety, and
70. Hopfner M, Huether A, Sutter AP, et al. Blockade of IGF-1 pharmacokinetic study of AVE1642, a human monoclonal
receptor tyrosine kinase has antineoplastic effects in hepa- antibody inhibiting the insulin-like growth factor-1 recep-
tocellular carcinoma cells. Biochem Pharmacol 2006; 71: tor (IGF-1R/CD221), administered as single agent and in
1435–48. combination with sorafenib as first line therapy in patients
71. Bekaii-Saab T, Markowitz J, Prescott N, et al. A multi- with advanced hepatocellular carcinoma (HCC). Presented
institutional phase II study of the efficacy and tolerability of in ASSLD, Boston, 2010, in press.




86. Laurent-Puig P, Legoix P, Bluteau O, et al. Genetic altera- 89. Carr BI, Hayashi I, Branum EL, Moses HL. Inhibition of DNA
tions associated with hepatocellular carcinomas deﬁne synthesis in rat hepatocytes by platelet-derived type beta
distinct pathways of hepatocarcinogenesis. Gastroenterology transforming growth factor. Cancer Res 1986; 46: 2330–4.
2001; 120: 1763–73. 90. Kanzler S, Meyer E, Lohse AW, et al. Hepatocellular
87. Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and expression of a dominant-negative mutant TGFbeta type
beta-catenin signalling: diseases and therapies. Nat Rev II receptor accelerates chemically induced hepatocarcino-
Genet 2004; 5: 691–701. genesis. Oncogene 2001; 20: 5015–24.
88. Nakamura T, Tomita Y, Hirai R, et al. Inhibitory effect of 91. Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, et al.
transforming growth factor-beta on DNA synthesis of adult Transforming growth factor-beta induces senescence in
rat hepatocytes in primary culture. Biochem Biophys Res hepatocellular carcinoma cells and inhibits tumor growth.
Commun 1985; 133: 1042–50. Hepatology 2010; 52: 966–74.

160

Liver International 2011

Empfohlen

Empfohlen

Weitere ähnliche Inhalte

Was ist angesagt?

Was ist angesagt? (20)

Andere mochten auch

Andere mochten auch (20)

Ähnlich wie Liver International 2011

Ähnlich wie Liver International 2011 (20)

Liver International 2011