SEARCH

SEARCH BY CITATION

Keywords:

  • biologic;
  • hepatocellular carcinoma;
  • review;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Therapy targeting angiogenesis
  5. Therapy targeted at growth signal transduction
  6. Therapy targeting at epigenetic dysregulation
  7. Future directions
  8. Conclusions
  9. Acknowledgment
  10. References

Following the encouraging results of sorafenib in advanced hepatocellular carcinoma (HCC), targeted therapy has become a new direction of research in the treatment of HCC. Emerging data provide evidence that the pathogenesis and progression of HCC are mediated by a number of molecular defects and dysregulated pathways. Novel targeted therapies are designed to inhibit the aberrant pathways at a molecular level with an aim to improve the clinical outcome. For the past few years, an increasing number of targeted agents have been tested in HCC in the clinical setting. This review aims to summarize the current status of clinical development of targeted therapy in HCC, with focus on novel agents targeting angiogenesis, signal transduction and epigenetic dysregulation of tumors. The review also discusses the lessons learned from outcomes of completed clinical trials and provides perspectives on future clinical trials in HCC.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Therapy targeting angiogenesis
  5. Therapy targeted at growth signal transduction
  6. Therapy targeting at epigenetic dysregulation
  7. Future directions
  8. Conclusions
  9. Acknowledgment
  10. References

Hepatocellular carcinoma (HCC) remains a major health problem worldwide. The disease is the sixth most common cancer and third leading cause of cancer-related mortality globally.1 HCC characteristically occurs in the background of cirrhotic liver of which chronic viral hepatitis B and C infection are the most important etiologies.2 Approximately 20–30% of patients with HCC present with early-stage disease that is amenable to resection or loco-ablative therapy, such as radiofrequency ablation.3,4 Another 20% of patients are diagnosed with multifocal intra-hepatic tumors; for these patients, trans-arterial chemoembolization (TACE) has been considered a standard treatment with the best efficacy being observed in patients without portal vein thrombosis.5,6

Systemic therapy is indicated when patients suffer from HCC with vascular or extra-hepatic involvement or progressive disease, which is not amenable to further locoregional therapy.3,7 It is estimated that up to half of HCC patients would eventually become candidates for systemic therapy.8,9 Conventionally, cytotoxic chemotherapy has been the mainstay of systemic treatment for HCC, especially in some Asian countries. Single agent doxorubicin is associated with a radiologic response rate of 10%, with more than 30% achieving reduction of serum α-fetoprotein level.10,11 However, the tolerability to chemotherapy is a concern in the cirrhotic population, and the complications of cirrhosis, including impaired liver function and thrombocytopenia, have rendered a significant proportion of patients not suitable for chemotherapy. As a result, cytotoxic chemotherapy has not been widely accepted as a standard systemic therapy for HCC in many centers.

In contrast to cytotoxic chemotherapy, targeted therapy aims at aberrant molecular pathways that are involved in carcinogenesis. Recently, two phase III randomized clinical trials have shown that sorafenib, a multi-targeted tyrosine kinase inhibitor, improves the overall survival of patients with advanced HCC.12,13 These results have not only led to approval of sorafenib as the standard systemic treatment for HCC, but also have unveiled a new era of development of targeted therapy for this disease. As the knowledge of molecular events accounting for progression of HCC advances, more targeted agents are being developed and tested in HCC. This review aims to summarize the important data about novel targeted agents for advanced HCC. Future directions for the development of targeted therapy for HCC will also be highlighted.

Therapy targeting angiogenesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Therapy targeting angiogenesis
  5. Therapy targeted at growth signal transduction
  6. Therapy targeting at epigenetic dysregulation
  7. Future directions
  8. Conclusions
  9. Acknowledgment
  10. References

Hepatocellular carcinoma is characterized by its hypervascularity and tendency to invade vasculature. The angiogenesis in HCC is mediated by a complex network of growth factors acting on both tumor cells and endothelial cells, as illustrated schematically in Figure 1. Vascular endothelial growth factor (VEGF) is the most studied mediator. It exerts its effects via binding to VEGF receptors (VEGFRs) of which there are three: VEFGR 1, 2 and 3. Most angiogenic phenotypes are mediated by VEGFR2.14 In patients with HCC, the expression of VEGF is associated with higher tumor grade and vascular invasion.15 Also, a higher circulating of VEGF level is associated with poorer prognosis after surgery and loco-ablative procedures for HCC.16,17 These data suggest that VEGF-mediated angiogensis is an important process for hepatocarcinogeneis.

image

Figure 1. Schematic diagram of key angiogenic factors/receptors and the site of action of anti-angiogenic therapy in hepatocellular carcinoma (HCC). Ang, Angiopoietin; FGF[R], fibroblast growth factor [receptor]; PDGF[R], platelet derived growth factor [receptor]; Tie2, Tyrosine kinase with immunoglobulin-like and EGF-like domains 1; VEGF[R], vascular endothelial growth factor [receptor]].

Download figure to PowerPoint

Apart from VEGF, the angiogenic process in HCC is mediated by the interaction of a number of factors including the platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and angiopoietin 1 and 2 with their respective receptors.18 In brief, PDGF is involved in the development of immature tumor vessels19 while angiopoietins exert their action via stabilization of vessels by recruiting surrounding pericytes and smooth muscle cells.20 Details of these angiogenic factors and their related physiological functions are beyond the scope of this review, and interested readers can refer to the review by Zhu et al.14 From a therapeutic point of view, inhibition of these targets has been shown to diminish the vascularity of tumors in preclinical studies,21 highlighting the potential additional benefits of inhibiting these targets apart from inhibition of VEGFR. Moreover, the upregulation of FGF has been suggested to be a resistance mechanism to anti-VEGFR therapy.22 Hence, blocking the FGF receptor (FGFR) is another potential important approach for clinical development in the treatment of HCC.

Two anti-angiogenic approaches have been developed in HCC; namely, small molecules and monoclonal antibodies. Small molecules are oral kinase inhibitors of low molecular weight. Their targets are usually tyrosine kinases at transmembrane receptors or at intracellular signaling molecules. Because of similarity in structures of kinase domains in different signaling molecules, small molecules are frequently multi-targeted, exhibiting different binding affinities to various receptors or intracellular signaling molecules. The second approach involves the use of monoclonal antibodies. These are recombinant antibodies with their antigen binding parts designed to cover the therapeutic target. Their targets are usually transmembrane receptors or extracellular circulating factors. Monoclonal antibody therapy is usually administered via the parenteral route.

Small molecule kinase inhibitors

Sorafenib is a multi-targeted small molecule, which inhibits the activity of VEGFR, PDGFR, B-Raf serine-theonine kinase, Fms-related tyrosine kinase (Flt) and c-kit at nanomolar concentration. The exact mechanism how sorafenib exerts its action on HCC remains unclear. Recent evidence suggests that the sorafenib mediates its anti-tumor activity mainly via blockade of VEGFR rather than by inhibition of Raf activity.23,24 Based on data from two phase III clinical trials comparing sorafenib to placebo, sorafenib improves the overall survival from 7.9 to 10.7 months in Caucasians with HCC, and from 4.2 to 6.5 months in Asians with HCC.12,13 Following the positive results of sorafenib in advanced HCC, a phase III clinical trial is currently undertaken to evaluate the adjuvant use of sorafenib in patients after resection of HCC. (ClinicalTrials.gov identifier: NCT00692770) Sorafenib has also been tested in combination with cytotoxic chemotherapy. In particular, Abou-Alfa et al. reported an impressive overall survival of 13.7 months with the combination of sorafenib and doxorubicin, which was significantly better than 6.5 months observed in the doxorubicin arm in a randomized phase II clinical trial.25 This combinational regimen is currently being tested in an ongoing phase III trial using sorafenib as a control. (NCT01015833).

Apart from sorafenib, a number of multi-targeted anti-angiogenic tyrosine kinase inhibitors that primarily target against VEGFR, such as sunitinib, linifanib, axitinib, cediranib, pazopanib, vandetanib and regorafenib, are currently under clinical development against advanced HCC26–30 (Fig. 1). The published phase II or phase III data of these anti-angiogenic agents are summarized in Table 1. It appears that class effects may not necessarily apply to small molecules with a similar panel of targets. For example, sunitinib, another oral multi-kinase inhibitor against VEFRs and PDGFRs, had reported tumor activity in the early phase II clinical trials with disease control rate ranging from 38% to 52% and overall survival ranging from 8.0 to 9.8 months.33,34 However, direct comparison of sunitinib with sorafenib in a phase III randomized trial was stopped prematurely because of inferior overall survival (7.9 vs 10.2 months; P = 0.0010) in the sunitinib arm.32 In the study, sunitinib was associated with more toxicities and the major complications (Grade 3 or above) included bleeding events (12%), thrombocytopenia (30%) and neutropenia (25%).32 This could have led to suboptimal dosing and thus worse outcomes in the sunitinib arm. Early termination of this study has basically prevented further investigation of sunitinib in treatment of HCC.

Table 1.  Summary of published Phase II or III clinical trials on anti-angiogenic targeted therapy in advanced hepatocellular carcinoma
AgentPhase (n)Efficacy (PFS/OS)RemarksReferences
  1. Data assessed in November 2011.

  2. HCC, hepatcellular carcinoma; m, months; OS, overall survival; PFS, progression-free survival.

Small molecule    
 Sorafenib    
  SorafenibIII (n = 602)5.5 m/10.7 m1st line in Caucasian HCC12
  Placebo2.8 m/7.9 m
  SorafenibIII (n = 271)2.8 m/6.5 m1st line in Asian HCC13
  Placebo1.4 m/4.2 m
  SorafenibII (n = 137)4.2 m/9.2 m 31
  Sorafenib + doxorubicinII (n = 96)6 m/13.7 m 25
  Placebo + doxorubicin2.7 m/6.5 m
Sunitinib    
 SunitinibIII (n = 1074)3.6 m/7.9 mStopped prematurely due to inferior outcome in sunitinib arm32
 Sorafenib3.0 m/10.2 m
 SunitinibII (n = 34)3.9 m/9.8 m37.5 mg/day (4 week on/2 week off)33
 SunitinibII (n = 37)3.7 m/8.0 m50 mg/day (4 week on/2 week off); pronounced toxicity observed34
LinifanibII (n = 44)3.7 m/9.7 m 26
CediranibII (n = 28)2.8 m/5.8 mDose at 45 mg daily; another phase II study (30 mg daily) is ongoing30
BrivanibII (n = 55)2.7 m/10.0 m1st line therapy35
TSU-68II (n = 35)2.1 m/13.1 m1st line therapy36
Other agents undergoing early clinical developmentPazopanib (Phase I); Axitinib (Phase II); Vatalanib (Phase I; further development stopped due to industry decision); Regorafanib (Phase II); Dovitinib (Phase II)
Monoclonal antibody    
 Bevacizumab    
  BevacizumabII (n = 46)6.9 m/12.4 mGrade 3 hemorrhage in 11% patients37
  Bevacizumab + gemcitabine/oxaliplatinII (n = 33)5.3/9.6 m 38
  Bevacizumab + erlotinibII (n = 40)9 m/15 mCaucasian HCC39
  Bevacizumab + erlotinibII (n = 27)3 m/9.5 mCaucasian HCC40
  Bevacizumab + capecitabineII (n = 45)3.6 m/8.2 mAsian HCC41
 Other monoclonal antibody undergoing early developmentRamucirumab (Phase II)

Since FGFR-mediated signaling is related to resistance to anti-VEGFR therapy, there exists a rationale to design agents to block both VEGFR and FGFR-mediated signals simultaneously. At present, there are three multi-targeted small molecules with activity covering both VEGFR and FGFR, namely brivanib, TSU-68 and dovitinib (Fig. 1). Brivanib is a dual VEGFR and FGFR inhibitor.42 Brivanib has been evaluated as a first-line agent in advanced HCC by a phase II study.35 This reported a median overall survival of 10 months and time to progression of 2.8 months.35 Major toxicities included fatigue, hypertension and transaminitis but few patients experienced Grade 3 or higher adverse effects.35 In the second line setting, a phase II study with brivanib has also reported modest activity with time to progression of 1.4 months in HCC patients who failed previous anti-angiogenic therapy.43 These results are yet to be confirmed by two ongoing phase III studies. The first (BRISK-FL study; NCT 00858871) is a head-to-head comparison of brivanib with sorafenib in the first-line setting, and another (BRISK-PS study; NCT00825955) is a placebo-controlled study evaluating the use of brivanib in the second-line setting. TSU-68 is an oral TKI against VEGFR, PDGFR and FGFR.44 This drug inhibits angiogenesis and induces significant tumor regression in preclinical models.44,45 A phase I/II study has demonstrated potential anti-tumor activity of TSU-68 in advanced HCC:36 Kanai et al. has reported phase II data of TSU-68 in 35 patients with disease stabilization rate of 48.5% and time to progression of 2.1 months.36 The activity shown in this study has warranted further clinical development of TSU-68. Dovitinib is another multi-targeted agent with activity against VEGFR, PDGFR, FGFR, Flt-3 and c-kit,46 and the drug demonstrated potent in vitro and in vivo activity in HCC.47 Its activity is currently being evaluated by an ongoing phase II randomized study comparing the agent to sorafenib as the first-line treatment for patients with Barcelona Clinic Liver Classification Stage C HCC. The results from these clinical trials will help determine whether additional blockage of FGFR is beneficial to patients with HCC.

Monoclonal antibodies

Bevacizumab is a recombinant humanized monoclonal antibody acting against VEGF, and is the first monoclonal antibody in this class to be tested against HCC. The agent has been evaluated as a single agent and in combination with other drugs in phase II studies (Table 1). According to a phase II study, bevacizumab possesses mild to moderate activity in HCC,37 which is associated with radiologic response rates of 10–20%. However, bevacizumab is potentially associated with severe hemorrhagic complications in cirrhotic patients; the rate was up to 11%.37 It is generally considered that the overall clinical benefit of bevacizumab is yet to be confirmed in larger scale studies before advocating its use in advanced HCC. Ramucirumab acts by binding directly to VEGFR2. Zhu et al. reported preliminary data on the activity of ramucirumab in a single-arm phase II study.48 with a disease control rate of 50%, and progression-free survival over 4 months.48 A phase III clinical trial comparing the use of ramucirumab to placebo in sorafenib-refractory patients is under way (NCT01140347).

Combination of anti-angiogenic therapy with TACE

There are two main reasons to support the combination of anti-angiogenic targeted therapy and TACE. First, TACE-induced tumor hypoxia upregulates angiogenic factors, including circulating VEGF.49,50 It has been demonstrated that the surge of VEGF level occurs as early as a few hours after the TACE procedure,49 and combining anti-angiogenic therapy with TACE could lead to reduction in VEGF level and vessel density in preclinical models.51 Second, TACE does not induce complete necrosis; the peripheral part of the tumor is frequently detected to be viable after the procedure through the process of revascularization.17 Application of anti-angiogenic therapy could theoretically improve the outcome by slowing down the angiogenic processes between cycles of TACE. This approach is currently under investigation by several groups;52–54 the completed and ongoing clinical trials are summarized in Table 2.

Table 2.  List of current and ongoing clinical trials on combinational antiangiogenic therapy and transarterial chemoembolization (TACE)
Study/phaseDesign and trial site (sample size for published works)Mode and time of targeted therapyStatusReferences/ClinicalTrials.gov identifier
Sorafenib    
 S-TACE Phase ISingle arm Swiss study (n = 14)Continuous with TACEPublished52
 SOCRATES Phase IISingle arm Germany studyInterrupted (withheld 3 days before and started 1 day after TACE)OngoingNCT00618384
 START Phase IISingle arm Multicentered Asian studyInterrupted (withheld 3 days before and started 3 days after TACE)OngoingNCT00990860
 Phase IISingle arm US study (n = 35)Interrupted (started at 1 week after TACE)Published54
 Phase IISingle arm Korean studyContinuous with TACEOngoingNCT01170104
 Phase IISingle arm Korean studyOne cycle of TACE followed sorafenibOngoingNCT00919009
 Phase IIRandomized (Sorafenib vs placebo) Multicetered UK studyContinuous with TACEOngoingNCT01324076
 TACTICS Phase IIRandomized (Open label) Japanese studyInterrupted (withhold 2 days and started 3 days after TACE)OngoingNCT01217034
 SPACE Phase IIIRandomized (Sorafenib vs placebo) MulticenteredContinuous with TACEAccrual completedNCT00494299
 Phase IIIRandomized (Sorafenib vs placebo) Multicentered Japanese/Korean study (n = 458)Delayed (started at 1–3 months after TACE)Completed53
 ECOG 1208 Phase IIIRandomized (Sorafenib vs placebo) MulticenteredInterrupted (withheld 24–48 h before and started 7–14 days after TACE)OngoingNCT01004978
Brivanib    
 BRISK TA Phase IIIRandomized (Brivanib vs placebo) MulitcenteredDelayed (Adjuvant) after TACEOngoingNCT00908752
Axitinib    
 Phase IISingle arm Hong Kong studyInterrupted (withheld 24 h before and resumed 24 h after TACE)OngoingNCT01352728

According to the currently available data, the timing of starting anti-angiogenic therapy in relation to TACE appears to be crucial to the outcome of treatment.55 From a randomized study comparing the use of sorafenib to placebo, the commencement of sorafenib at 1–3 months after TACE failed to demonstrate any survival benefit,53 while another phase II study conducted by Pawlik et al. reported promising radiologic response rates (disease control rate of 95% according to response evaluation criteria in solid tumor and objective response rate of 58% according to European Association for the Study of the Liver criteria) when sorafenib was started just one week after TACE.54 Our group is currently looking at the efficacy and safety of starting antiangiogenic agent, axitinib, in combination with TACE (NCT01352728). Regarding the trial design, patients who are candidates for TACE are started on axitinib for 4 weeks before TACE. In this clinical trial, axitinib is withheld 24 h before TACE and started 24 h after completion of TACE when there are no grade 3 toxicities from TACE. With more mature data from ongoing studies, it is anticipated that the most optimal way of combining TACE with anti-angiogenic agents can be clarified.

Therapy targeted at growth signal transduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Therapy targeting angiogenesis
  5. Therapy targeted at growth signal transduction
  6. Therapy targeting at epigenetic dysregulation
  7. Future directions
  8. Conclusions
  9. Acknowledgment
  10. References

Apart from angiogenesis, hepatocarcinogenesis is mediated and maintained by a network of dysregulated growth signaling pathways. These are generally involved in the proliferation, invasion and metastases of cancer. In terms of mechanism, growth signaling transductions are typically initiated by binding of growth factors to their cognate receptors on the cellular membrane, and this binding activates a signaling cascade of intracellular molecules (Fig. 2). As a result, these receptors and the associated pathways have become therapeutic targets for cancer treatment. The development of these agents at different phases and on different pathways for HCC is summarized in Table 3. In the following section, some of the important therapeutic targets in various signaling pathways are discussed.

image

Figure 2. Illustration of the important growth signaling pathways involved in hepatocarcinogenesis and the related targeted therapy under clinical development in hepatocellular carcinoma (HCC). EGF[R], epidermal growth factor [receptor]; ERK, extracellular-signal-regulated kinase; GDP, guanosine diphosphate; HDAC, histone deacetylase; HGF, hepatocyte growth factor; mTOR, MEK, mitogen-activated extracellular-signal regulated kinase kinase; Mammalian Target of Rapamycin; P, phosphorylation; PIP2, Phosphatidylinositol 4,5-bisphosphate; PIP3, Phosphatidylinositol (3–5)-trisphosphate; PTEN, phosphatase and tensin homolog; SOS, son of sevenless; Grb2, growth factor receptor-bound protein 2; PI3K, Phosphatidylinositol 3-Kinase.

Download figure to PowerPoint

Table 3.  Targeted therapy (other than anti-angiogenic agents) undergoing clinical evaluation in hepatocellular carcinoma (HCC)
Mechanism/pathwayTargetAgentLatest phase of clinical development
  1. Data Assessed in November 2011.

  2. Bcl2, B-cell lymphoma 2; EGFR, Epidermal growth factor receptor; ERK, extracellular-signal-regulated kinase; GPC3, Glypican-3; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IGFR, insulin-like growth factor receptor; MEK, mitogen-activated protein kinase/ERK kinase; mTOR, mammalian Target of Rapamycin, PI3K, Phosphatidylinositol 3-Kinase; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.

EGFREGFRCetuximabII
ErlotinibIII
GefitinibII
LapatinibII
HGF/c-METc-METARQ197II
ForetinibI
PI3K/Akt/mTORAktMK2206I
mTORTemsirolimusII
EverolimusIII
AZD8055I
RapamycinIII
Raf/MEK/ERKRAFSorafenibIV
MEKAZD6244II
IGFIGFRCixutumumabII
AVE1642II
BIIB022II
OSI-906II
Epigenetic dysregulationHistone DeacetylaseBelinostatII
Panobinostat (LBH589)I
ResminostatII
VorinostatI
ApoptosisTRAILMapatumumabII
BCL2OblimersenII
OthersProteasomeBortezomibII
GPC3GC333II

Epidermal growth factor receptor

Epidermal growth factor receptor (EGFR) is among the best described therapeutic targets in cancer, and targeting EGFR has proved successful in lung and colorectal cancers. Pre-clinical evidence indicated that EGFR-related signaling is involved in hepatocarcinogensis.56 Similar to anti-angiogenic therapy, two therapeutic anti-EGFR approaches exist. First, use of the monoclonal antibody against EGFR, Cetuximab, has been tested as a single agent in two phase II studies.57,58 Both studies reported minimal activity: no responses were seen and the progression-free period was shorter than 2 months in both studies.57,58 Second, a number of small molecules have also been tested in early clinical trials, including erlotinib, gefitinib and lapatinib.59–62 However, all of these trials also failed to demonstrate significant activity against HCC. Considering all of the clinical data, anti-EGFR therapy as a single agent is considered not useful in the treatment of advanced HCC. The exact reason for the minimal activity of anti-EGFR therapy in HCC remains unclear. However, one of the possible reasons could be due to the lack of activating mutations in EGFR in HCC, which predicts clinical responses to anti-EGFR small molecules in non-small cell lung cancer.63

On the other hand, the combination of erlotinib and sorafenib was found to be synergistic in growth inhibition and induction of apoptosis of cancer cells.64 In addition, a phase I clinical trial has found this combinational regimen to be active and tolerable in patients with solid tumors.65 Based on this evidence, a phase III clinical trial has been commenced to determine the efficacy and tolerability of the combined regimen of erlotinib and sorafenib in HCC (NCT00901901). Another combinational regimen, erlotinib and bevacizumab, has also been tested in a number of phase II studies in patients of different ethnicities. Thomas et al. reported an overall survival of 15 months with erlotinib and bevacizumab in 40 Caucasian HCC patients.39 However, other phase II study failed to reproduce the same survival data with a similar regimen in another study in Caucasian populations (median progression-free/overall survival = 3/9.5 months).40 Therefore, anti-EGFR therapy based combinations should not be used routinely in clinical management of advanced HCC before further data from phase III studies are available.

Phosphatidylinositol 3-kinase/Akt/mammalian Target of Rapamycin pathway

The phosphatidylinositol 3-kinase/Akt/mammalian Target of Rapamycin (PI3K/Akt/mTOR) axis is involved in multiple cellular processes including survival and proliferation.66 This pathway is initiated when membrane receptors are activated by binding of growth factors, which in turn recruit and activate the phosphoinositide 3-kinase (PI3K). The activation of PI3K will lead to a cascade of activation of downstream effectors including serine-threonine kinases Akt and mTOR (Fig. 2). Comprehensive genomic analyses have shown that components of the PI3K/Akt/mTOR pathway are frequently dysregulated in HCC.67,68 In fact, it has been demonstrated that aberrations of the pathway occur in 40–50% of HCC.67 Moreover, the activation of downstream effectors of mTOR, including 4E-BP1 and S6K1, are reportedly associated with higher tumor grade of HCC.69 Therefore, targeting the components along the PI3K/Akt/mTOR axis has been a research focus in developing novel targeted therapy for HCC.

The agents targeting the PI3K/Akt/mTOR pathway currently undergoing clinical development are summarized in Table 3. Agents have been designed to target the PI3K, Akt and mTOR respectively, and both Akt and mTOR inhibitors are being tested in HCC. The mTOR inhibitor everolimus has demonstrated clinical activity in HCC patients. According to a phase I/II study in 28 patients with advanced HCC, among which more than 70% had been treated with more than one regimen, everolimus demonstrated activity with disease control rate of 44% and an overall survival of 8.4 months.70 Also, everolimus was well tolerated with the most common side effects being fatigue and hyperglycaemia.70 Currently, a phase III EVOLVE-1 study comparing everolimus to placebo is ongoing in patients who have failed sorafenib treatment (NCT01035229).

Another intravenously administered mTOR inhibitor, temsirolimus, has also been tested in a phase II setting by our group (NCT01251458). The trial has already completed accrual, and the results are anticipated to be available shortly in the future.

Hepatocyte growth factor/c-MET

Hepatocyte growth factor (HGF) is secreted by stromal cells, and c-MET is the high-affinity tyrosine kinase receptor for HGF (Fig. 2). The c-MET receptor is coupled with a number of downstream intracellular signaling pathways including the PI3K/Akt/mTOR and mitogen-activated protein kinase (MAPK)/ERK pathways. Under physiological conditions, HGF does not have a significant role in liver homeostasis. However, after hepatic injury, HGF is heavily involved in liver regeneration and tissue remodeling.71,72 In surgical specimen, c-MET overexpression was observed in about 20–48% of samples, and this was associated with worse outcome among patients with HCC.73–75

Inhibition of HGF/c-MET signaling has been explored as a therapeutic strategy for advanced HCC. ARQ 197 is the first c-MET tyrosine kinase inhibitor undergoing clinical development in HCC. A phase I clinical trial testing ARQ 197 in HCC patients with Childs' A and B function reported preliminary data of time to progression of 3.5 months and manageable toxicity profile, mainly 43% anemia and 38% neutropenia of all grades.76 A randomized phase II trial comparing the agent to placebo in patients who had failed first-line systemic therapy is ongoing (NCT00988741).

Another c-MET inhibitor, Foretinib, is currently undergoing clinical development in HCC (ClinicalTrials.gov identifier: NCT00920192). For the treatment of HCC, two important questions about c-MET inhibitors need to be addressed. First, c-MET is simultaneously involved in maturation of bone marrow progenitor cells. It remains to be determined whether marrow toxicity is a significant issue in HCC patients, who frequently suffer from co-morbidity of cirrhosis and/or portal hypertension. Second, preclinical models have clearly demonstrated that cell lines lacking c-MET expression do not respond to c-MET inhibitor.77 As a result, it has been proposed that the c-MET expression could be used as a predictive biomarker for treatment response. It is therefore pivotally important for future clinical trials to evaluate whether c-MET expression is a predictive biomarker for c-MET inhibitor.

Other emerging signaling pathways

In addition to EGFR, PI3K/Akt/mTOR and HGF/c-MET mediated pathways, an increasing number of growth signaling pathways are found to be involved in the pathogenesis of HCC. For example, the RAF/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) pathway has been found to be frequently dysregulated in HCC by processes not due to RAF mutation.78 This highlights the need for blocking downstream molecules of the pathway such as MEK. MEK inhibitor, selumatinib (AZD 6244), has recently been available for testing in HCC in the clinical setting.79

Insulin growth factor receptor (IGFR) signaling is another pathway that is involved in the development and progression of HCC. Therapeutics targeting at IGFR pathway have also been under development in early clinical trials.80 The Wnt/beta-catenin signaling pathway is another emerging mechanism that is involved in the regulation of cancer stem cells of HCC under hypoxic conditions.81 Although therapeutics targeting Wnt/beta-catenin pathways are not yet available for clinical testing at present, some small molecule compounds such as XAV939 and pyrvinium have already been indentified,82,83 and it is anticipated that these agents will be tested clinically in the future.

Therapy targeting at epigenetic dysregulation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Therapy targeting angiogenesis
  5. Therapy targeted at growth signal transduction
  6. Therapy targeting at epigenetic dysregulation
  7. Future directions
  8. Conclusions
  9. Acknowledgment
  10. References

Apart from genetic defects, epigenetic mechanisms play a pivotal role in hepatocarcinogenesis. Epigenetic mechanism generally refers to any modification of expression of genome without alteration in the nucleotide sequence. Well studied mechanisms include both hypermethylation and histone acetylation.84 During cancer development, aberrant methylation typically takes place at cytosine of cytosine-guanine dinucleotide (CpG) islands clustered around promoter regions, and is associated with downregulation of tumor suppressor genes. It has been demonstrated that there is stepwise increase of methylation events in CpG islands along the progression of dysplastic nodules to HCC, suggesting that methylation events participate in transformation and proliferation of HCC.85 On the other hand, the expression of tumor suppressor gene is influenced by coiling and uncoiling of DNA around histone, and this is mainly mediated via histone acetylation. Acetylation of histone results in less condensed chromatin and gene expression, while histone deacetylases (HDAC) remove the acetyl groups from histone leading to condensed and transcriptionally silenced chromatin. (Fig. 3)

image

Figure 3. Mechanism of histone deacetylase inhibitor in the treatment of cancer. HAT, histone acetyltransferase; HDAC, histone deacetylase.

Download figure to PowerPoint

Epigenetic deregulation is distinct from other genetic mechanisms because it is reversible by targeted therapeutics such as DNA methyltransferase inhibitor and/or HDAC inhibitor. Epigenetic therapeutics have emerged as an active class of anticancer agents in hematological malignancies. Azacitinine, a DNA methyltransferase inhibitor, has been approved in the treatment of myelodysplastic syndrome.86 Two HDAC inhibitors, vorinostat and romidepsin, have also been approved for the treatment of peripheral T-cell lymphoma.87,88 In HCC, HDAC is the first inhibitor to be investigated. Preclinical studies showed that treatment with this inhibitor could induce apoptosis in HCC models.89–91 Our group has recently completed a National Cancer Institute phase I/II study using belinostat, a HDAC inhibitor, in advanced HCC (NCT00321594). Preliminary data demonstrated clinical responses and good safety profile in a heavily pre-treated population of HCC.92 In the phase II portion of 42 patients, 38% of them have received more than one line of systemic therapy. Preliminary data demonstrated clinical activity with disease stabilization rate of 47.6%, progression-free survival of 2.64 months and overall survival of 6.6 months.92 Belinostat is generally well tolerated with less than a 10% rate of Grade 3 or higher toxicities. In view of the good tolerance, further study is warranted to explore the clinical efficacy of epigenetic therapy in combination with other drugs in the treatment of HCC.

Future directions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Therapy targeting angiogenesis
  5. Therapy targeted at growth signal transduction
  6. Therapy targeting at epigenetic dysregulation
  7. Future directions
  8. Conclusions
  9. Acknowledgment
  10. References

Despite initial encouraging results from sorafenib, the development of targeted therapeutics for HCC remains a daunting task. It is not infrequent to encounter novel agents that work well in preclinical models of HCC but fail to produce significant clinical benefits. This is most likely due to incomplete understanding of the complexity of the mechanisms involved in progression of HCC. It is also clear that there is high heterogeneity in HCC tumors and different etiological factors may be associated with various driving genetic defects or pathways. Experience from the lung and breast cancer fields have shown that success in clinical trials on targeted therapy can only be improved if we are able to apply an agent to a group of appropriately selected patients whose tumors are “addicted” to a known driver gene or pathway.

At present, a number of projects based on different sequencing or microarray platforms are being conducted to decipher the molecular profiles and classification of HCC.93 It is anticipated that the results could facilitate the development of personalized targeted therapy for patients with HCC. On the other hand, the accomplishment of personalized therapy will likely have to rely on the identification of tissue biomarkers in HCC. Currently, most guidelines recommend against histological diagnosis of HCC when the tumor expresses characteristic vascular patterns on dynamic imaging. As a result, most clinical trials on targeted therapy in HCC do not have tumor tissue to validate potential predictive biomarkers. Given the emergence of various targeted agents undergoing testing in the clinical setting, the availability of histological sample, preferably via core needle biopsy before treatment, should be seriously considered in suitable patients during the design of a clinical trial.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Therapy targeting angiogenesis
  5. Therapy targeted at growth signal transduction
  6. Therapy targeting at epigenetic dysregulation
  7. Future directions
  8. Conclusions
  9. Acknowledgment
  10. References

Targeted therapy for HCC is currently under intensive investigation. The story of sorafenib has proven the concept that targeted therapy brings benefits to patients with HCC, although at present these remain limited. At present, a number of novel agents targeting at the angiogenesis of HCC have already been tested or are under phase III development. Some of these studies have already completed accrual while others are ongoing. It is anticipated that more robust clinical data on novel anti-angiogenic agents will be available in the very near future. On the other hand, the development of therapy aiming at various growth signaling pathways is less advanced. mTOR inhibitors appear to be the most promising agents in this category. Finally, targeting epigenetic dysregulation is a relatively new concept in treatment of HCC. Epigenetic therapeutics have already been found to be efficacious in the treatment of a number of hematological cancers. From the currently available clinical data, HDAC inhibitor belinostat has demonstrated promising activity and tolerable toxicity profile in HCC, and further development of this class of agent is warranted.

Future directions of targeted therapy for HCC should be aimed at better understanding of various molecular events driving the progression of HCC as well as identification of biomarkers to predict treatment response of targeted agent in patients. In summary, success in the development of targeted agents for HCC relies on concerted efforts on testing of novel agents in clinical trials, advancement of knowledge on molecular classification of HCC and discovery of biomarkers to guide personalized treatment.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Therapy targeting angiogenesis
  5. Therapy targeted at growth signal transduction
  6. Therapy targeting at epigenetic dysregulation
  7. Future directions
  8. Conclusions
  9. Acknowledgment
  10. References