New molecularly targeted therapies against advanced hepatocellular carcinoma: From molecular pathogenesis to clinical trials and future directions

Hepatology Research

Volumn 45, Issue 10, 2015, Pages E1-E11

  Chuma, Makoto ^a,b,c   Terashita, Katsumi ^a   Sakamoto, Naoya ^a,c  

^a HOKKAIDO UNIVERSITY   (Japan)

^b YOKOHAMA CITY UNIVERSITY MEDICAL CENTER   (Japan)

^c NONE

Author keywords

Clinical trials; Hepatocellular carcinoma; Molecularly targeted therapy; Novel agents; Sorafenib

Indexed keywords

ALPHA CRYSTALLIN; ALPHA FETOPROTEIN; BIOLOGICAL MARKER; BRIVANIB; CABOZANTINIB; DECARBOXYPROTHROMBIN; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; EVEROLIMUS; FIBROBLAST GROWTH FACTOR; FIBROBLAST GROWTH FACTOR 3; FIBROBLAST GROWTH FACTOR 4; FIBROBLAST GROWTH FACTOR RECEPTOR; LENVATINIB; LINIFANIB; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; ORANTINIB; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN RET; RAMUCIRUMAB; REGORAFENIB; SORAFENIB; STRESS ACTIVATED PROTEIN KINASE; SUNITINIB; TIVANTINIB; TUMOR MARKER; VASCULOTROPIN A; VASCULOTROPIN RECEPTOR;

ANEMIA; ASTHENIA; BLEEDING; CANCER CHEMOTHERAPY; CANCER COMBINATION CHEMOTHERAPY; CANCER STAGING; CHEMOEMBOLIZATION; CHILD PUGH SCORE; DECREASED APPETITE; DIARRHEA; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; FATIGUE; GASTROINTESTINAL HEMORRHAGE; HAND FOOT SYNDROME; HEPATIC ARTERIAL INFUSION CHEMOTHERAPY; HUMAN; HYPERTENSION; HYPONATREMIA; HYPOPHOSPHATEMIA; LIVER CELL CARCINOMA; LIVER FUNCTION; MOLECULARLY TARGETED THERAPY; NEUTROPENIA; OVERALL SURVIVAL; PATHOGENESIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; THROMBOCYTOPENIA; UNSPECIFIED SIDE EFFECT; WEIGHT REDUCTION;

EID: 84945456021     PISSN: 13866346     EISSN: 1872034X     Source Type: Journal    
DOI: 10.1111/hepr.12459     Document Type: Review

References (63)

1. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142: 1264-1273.
2. Belghiti J, Fuks D. Liver resection and transplantation in hepatocellular carcinoma. Liver Cancer 2012; 1: 71-82.
3. European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-943.
4. Kim B, Kim S, Park J etal. Applicability of BCLC stage for prognostic stratification in comparison with other staging systems: single centre experience from long-term clinical outcomes of 1717 treatment-naïve patients with hepatocellular carcinoma. Liver Int 2012; 32: 1120-1127.
5. Llovet JM, Ricci S, Mazzaferro V etal. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390.
6. Cheng AL, Kang YK, Chen Z etal. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo controlled trial. Lancet Oncol 2009; 10: 25-34.
7. Guichard C, Amaddeo G, Imbeaud S etal. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 2012; 44: 694-698.
8. Villanueva A, Llovet JM. Liver cancer 2013: mutational landscape of HCC-the end of the beginning. Nat Rev Clin Oncol 2014; 11: 73-74.
9. Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med 1998; 49: 407-424.
10. Kumar P, Coltas I, Kumar B etal. Bcl-2 protects endothelial cells against gamma-radiation via a Raf-MEK-ERK-survivin signalingpathway that is independent of cytochrome c release. Cancer Res 2007; 67: 1193-1202.
11. Graupera M, Guillermet-Guibert J, Foukas L etal. Angiogenesis selectively requires the p110alpha isoform of PI3K to controlendothelial cell migration. Nature 2008; 453: 662-666.
12. Schoenleber SJ, Kurtz DM, Talwalkar JA etal. Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer 2009; 100: 1385-1392.
13. Kin M, Sata M, Ueno T etal. Basic fibroblast growth factor regulates proliferation and motility of human hepatoma cells by an autocrine mechanism. J Hepatol 1997; 27: 677-687.
14. Tsunoda S, Nakamura T, Sakurai H etal. Fibroblast growth factor 2- induced host stroma reaction during initial tumor growth promotes progression of mouse melanoma via vascular endothelial growth factor A-dependent neovascularization. Cancer Sci 2007; 98: 541-548.
15. Jain RK, Booth MF. What brings pericytes to tumor vessels? J Clin Invest 2003; 112: 1134-1136.
16. Sugimachi K, Tanaka S, Taguchi K etal. Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma. J Clin Pathol 2003; 56: 854-860.
17. Campbell JS, Hughes SD, Gilbertson DG etal. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci U S A 2005; 102: 3389-3394.
18. Crawford Y, Kasman I, Yu L etal. PDGFC mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 2009; 15: 21-34.
19. Lau DT, Luxon BA, Xiao SY etal. Intrahepatic gene expression profiles and alpha-smooth muscle actin patterns in hepatitis C virus induced fibrosis. Hepatology 2005; 42: 273-281.
20. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489-501.
21. Schmitz KJ, Wohlschlaeger J, Lang H etal. Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol 2008; 48: 83-90.
22. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol 2005; 23: 6771-6790.
23. Whittaker S, Marais R, Zhu AX. The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 2010; 29: 4989-5005.
24. You WK, McDonald DM. The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB Rep 2008; 41: 833-839.
25. Chan AM, Rubin JS, Bottaro DP etal. Identification of a competitive HGF antagonist encoded by an alternative transcript. Science 1991; 254: 1382-1385.
26. Yap TA, de Bono JS. Targeting the HGF/c-Met axis: state of play. Mol Cancer Ther 2010; 9: 1077-1079.
27. Ke AW, Shi GM, Zhou J etal. Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology 2009; 49: 491-503.
28. Kondo S, Ojima H, Tsuda H etal. Clinical impact of c-Met expression and its gene amplification in hepatocellular carcinoma. Int J Clin Oncol 2013; 18: 207-213.
29. Lee SJ, Lee J, Sohn I etal. A survey of c-MET expression and amplification in 287 patients with hepatocellular carcinoma. Anticancer Res 2013; 33: 5179-5186.
30. Cheng AL, Kang YK, Lin D-Y etal. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013; 31: 4067-4075.
31. Johnson P, Qin S, Park JW etal. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 2013; 31: 3517-3524.
32. Llovet JM, Decaens T, Raoul JL etal. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 2013; 31: 3509-3516.
33. Cainap C, Qin S, Huang WT etal. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2013; 31 (Suppl 4): abstr 249.
34. Zhu AX, Rosmorduc O, Evans J etal. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patientswith hepatocellular carcinoma. Ann Oncol 2012; 23 (Suppl 9): abstr LBA2.
35. Zhu AX, Kudo M, Assenat E etal. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 2014; 312: 57-67.
36. Zhu AX, Finn RS, Mulcahy M etal. A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer. Clin Cancer Res 2013; 19: 6614-6623.
37. Zhu AX, Ryoo B, Yen C etal. LBA16 - Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC) following first-line therapy with sorafenib: results from the randomized phase III REACH study. ESMO Congress 2014; abstr LBA16.
38. Koyama N, Saito K, Nishioka Y etal. Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib. BMC Cancer 2014; 14: 530.
39. Finn R, Cheng A, Ikeda K etal. A multicenter, open-label, phase III trial to compare the efficacy and safty of Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma. J Clin Oncol 2014; 32 (Suppl): abstr TPS4153.
40. Mross K, Frost A, Steinbild S etal. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res 2012; 18: 2658-2667.
41. Bruix J, Tak WY, Gasbarrini A etal. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer 2013; 49: 3412-3419.
42. Adjei AA, Schwartz B, Garmey E. Early clinical development of ARQ 197, a selective, non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers. Oncologist 2011; 16: 788-799.
43. Abou-Alfa GK, Venook AP. The antiangiogenic ceiling in hepatocellular carcinoma: does it exist and has it been reached? Lancet Oncol 2013; 14: e283-288.
44. Cohn AL, Kelley RK, Yang TS etal. Activity of cabozantinib (XL184) in hepatocellular carcinoma patients: results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 2012; 30 (Suppl): abstr 4007.
45. Verslype C, Cohn A, Kelley R etal. Activity of cabozantinib (XL184) in hepatocellular carcinoma: results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 2012; 30 (Suppl): abstr 4007.
46. Fernández M, Semela D, Bruix J etal. Angiogenesis in liver disease. J Hepatol 2009; 50: 604-620.
47. Kudo M, Imanaka K, Chida N etal. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011; 47: 2117-2127.
48. Kudo M, Han G, Finn RS etal. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial. Hepatology 2014; 60: 1697-1707.
49. Kanai F, Yoshida H, Tateishi R etal. A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2011; 67: 315-324.
50. Arao T, Ueshima K, Matsumoto K etal. FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma. Hepatology 2013; 57: 1407-1415.
51. Huang XY, Ke AW, Shi GM etal. αB-crystallin complexes with 14-3-3ζ to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma. Hepatology 2013; 57: 2235-2247.
52. Hagiwara S, Kudo M, Nagai T etal. Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma. Br J Cancer 2012; 106: 1997-2003.
53. Horwitz E, Stein I, Andreozzi M etal. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov 2014; 4: 730-743.
54. Abou-Alfa GK, Schwartz L, Ricci S etal. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: 4293-4300.
55. Miyahara K, Nouso K, Tomoda T etal. Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2011; 26: 1604-1611.
56. Yau T, Yao TJ, Chan P etal. The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib. Oncologist 2011; 16: 1270-1279.
57. Kuzuya T, Asahina Y, Tsuchiya K etal. Early decrease in α-fetoprotein, but not des-γ-carboxy prothrombin, predicts sorafenib efficacy in patients with advanced hepatocellular carcinoma. Oncology 2011; 81: 251-258.
58. Ueshima K, Kudo M, Takita M etal. Des-γ-carboxyprothrombin may be a promising biomarker to determine the therapeutic efficacy of sorafenib for hepatocellular carcinoma. Dig Dis 2011; 29: 321-325.
59. Miyahara K, Nouso K, Morimoto Y etal. Evaluation of the effect of sorafenib using serum NX-des-γ-carboxyprothrombin in patients with hepatocellular carcinoma. Hepatol Res 2013; 43: 1064-1070.
60. Tsuchiya K, Asahina Y, Matsuda S etal. Changes in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma. Cancer 2014; 120: 229-237.
61. Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res 2014; 20: 2072-2079.
62. Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol 2008; 48 (Suppl 1): S20-S37.
63. Chan SL, Mo FK, Wong CS etal. A study of circulating interleukin 10 in prognostication of unresectable hepatocellular carcinoma. Cancer 2012; 118: 3984-3992.