Published OnlineFirst October 1, 2018; DOI: 10.1158/1078-0432.CCR-18-1254 Review Clinical Cancer Research The Role of Angiogenesis in Hepatocellular Carcinoma Michael A. Morse1, Weijing Sun2, Richard Kim3, Aiwu Ruth He4, Paolo B. Abada5, Michelle Mynderse6, and Richard S. Finn7 Abstract Hepatocellular carcinoma (HCC) accounts for about 90% systemic treatments such as those targeting the vascular endo- of all primary liver cancers and is the second leading cause of thelial growth factor receptor and its ligand. However, the cancer-related deaths worldwide. The hypervascular nature of clinical relevance of other more recently identified angiogenic most HCC tumors underlines the importance of angiogenesis pathways in HCC pathogenesis or treatment remains unclear. in the pathobiology of these tumors. Several angiogenic path- Research into molecular profiles and validation of prognostic ways have been identified as being dysregulated in HCC, or predictive biomarkers will be required to identify the patient suggesting they may be involved in the development and subsets most likely to experience meaningful benefit from this pathogenesis of HCC. These data provide practical targets for important class of agents. Clin Cancer Res; 1–9. Ó2018 AACR. Introduction Angiogenesis and Angiogenic Targets in Hepatocellular carcinoma (HCC) is the second leading Advanced HCC cause of cancer mortality (1). Most patients with HCC present Hypoxia is presumed to robustly stimulate tumor angiogenesis with advanced disease (2), and the 5-year overall survival (OS) (17, 18). Several animal models examining the hypoxic tumor rates are 10% for locally advanced and 3% for metastatic microenvironment in HCC with small fiberoptic sensors or radio- disease (3). Although HCC follows diverse causes of liver graphic imaging with oxygen-sensitive probes have shown intra- damage (including chronic alcohol use, chronic hepatitis B tumor oxygen values that were significantly lower than those in and C infection, and nonalcoholic fatty liver disease; ref. 4), normal liver tissue (18–20). Direct evidence of hypoxia in human fi common associated ndings are hypervascularity and marked HCC is sparse, and results have not been as clear (21). Most HCC vascular abnormalities (5), such as arterialization and sinu- in vitro and in vivo models investigating hypoxia-mediated soidal capillarization (6). Increased tumor vascularity may mechanisms in HCC focus on the upregulation of hypoxia-induc- result from sprouting angiogenesis or by recruiting existing ible factor proteins, which induce expression of proangiogenic vessels into the expanding tumor mass (a process called factors, including vascular endothelial growth factor (VEGF), that co-option). This review addresses the molecular underpinnings promote angiogenesis in HCC tumors (17, 18, 22, 23). At the of angiogenesis in advanced HCC, current approaches to molecular level, angiogenesis results from an imbalance between targeting angiogenesis (Table 1), novel strategies in develop- drivers of vessel growth and maturation [VEGF-A, -B, -C, and -D, ment, and prospects for combining antiangiogenic therapy fibroblast growth factors (FGF), platelet-derived growth factors with other systemic modalities. (PDGF), angiopoietins, hepatocyte growth factor, endoglin (CD105), and others] and inhibitors (angiostatin, endostatin, thrombospondin-1, and others). Proangiogenic factors activate endothelial cell tyrosine kinases and subsequent downstream intracellular signaling through mitogen-activated protein kinase 1 Department of Medicine, Division of Medical Oncology, Duke University Health and phosphatidylinositol-3-kinases (PI3K)/Akt/mTOR pathways System, Durham, North Carolina. 2Division of Medical Oncology, University of Kansas School of Medicine, Kansas City, Kansas. 3Department of Gastrointestinal leading to angiogenesis (24). The complexity and potential syn- Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. ergism of these pathways that stimulate angiogenesis have 4Department of Medicine, Georgetown University Medical Center, Washington, prompted the development of multiple antiangiogenic therapies District of Columbia. 5Eli Lilly and Company, Indianapolis, Indiana. 6Syneos over the last several decades. 7 Health, Clinical Solutions, Raleigh, North Carolina. Department of Medicine, In fact, most currently approved treatments for advanced HCC Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los in the first- and second-line settings target angiogenic pathways. Angeles, California. Of the known or potential angiogenic pathways in tumors, the Note: Current address for M. Mynderse: PRA Health Sciences, Raleigh, North VEGF/VEGF receptor (VEGFR) signaling pathway has been vali- Carolina. dated as a drug target in HCC (7, 14). The first breakthrough Corresponding Author: Michael A. Morse, Department of Medicine, Division of systemic therapy for treating advanced HCC was sorafenib (4), a Medical Oncology, Duke University Health System, Duke Box 3233, Durham, NC multikinase inhibitor that disrupts VEGFR signaling as well as 27710. Phone: 919-681-3480; E-mail: [email protected] several other targets involved in angiogenesis (ref. 7; Table 1). doi: 10.1158/1078-0432.CCR-18-1254 Other molecular pathways that may have angiogenic effects Ó2018 American Association for Cancer Research. are specifically targeted by several agents under investigation www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. OF2 Clin Cancer Res; 2018 Morse et al. Downloaded from Table 1. Antiangiogenic therapies evaluated in phase III trials for treatment of HCC Published OnlineFirstOctober1,2018;DOI:10.1158/1078-0432.CCR-18-1254 mOS mPFS ORR DCR clincancerres.aacrjournals.org Compound Type Target(s) Phase Treatment line Regimen N (mos) HR (95% CI), P (mos) HR (95% CI), P (%) (%) Sorafenib (7) TKI VEGFR-1–3, PDGFR-b, III 1st line Sorafenib 299 10.7 0.69 (0.55–0.87), <0.001 5.5 0.58 (0.45–0.74), <0.001 2 43a c-Kit, FLT-3, RET, Raf- Placebo 303 7.9 2.8 1 32a 1, B-Raf Regorafenib (8) TKI VEGFR-1–3, PDGFR-b, III 2nd line Regorafenib 379 10.6 0.63 (0.50–0.79), <0.0001 3.1 0.46 (0.37–0.56), <0.0001 11b 65b,c FGFR1, CD117, RET, Placebo 194 7.8 1.5 4b 36b,c B-Raf, TIE2 Sunitinib (9) TKI VEGFR-1–3, PDGFR, III 1st line Sunitinib 530 7.9 1.30 (1.13–1.50), 0.0014 3.6 1.13 (0.99–1.30), 0.229 6.6 50.8d c-Kit, FLT-3, RET Sorafenib 544 10.2 3.0 6.1 51.5d Brivanib (10) TKI VEGFR, FGFR III 1st line Brivanib 577 9.5 1.07 (0.94–1.23), 0.312 4.2e 1.01 (0.88–1.16), 0.853 9b 65b Sorafenib 578 9.9 4.1e 12b 66b Brivanib (11) TKI VEGFR, FGFR III 2nd line Brivanib 263 9.4 0.89 (0.69–1.15), 0.331 4.2e 0.56 (0.42, 0.76), <0.001 10 61 Cancer Research. Placebo 132 8.2 2.7e 240 Linifanib (12) TKI VEGFR, PDGFR III 1st line Linifanib 514 9.1 1.05 (0.90–1.22), ns 5.4 0.76 (0.64–0.90), 0.001 13.0 NR on September 28, 2021. © 2018American Association for Sorafenib 521 9.8 4.0 6.9 NR Lenvatinib (13) TKI VEGFR-1–3, FGFR-1–4, III 1st line Lenvatinib 478 13.6 0.92 (0.79–1.06) 7.4 0.66 (0.57–0.77), <0.001 24.1b,f 75.5b,f PDGFR-a, RET, c-Kit Sorafenib 476 12.3 3.7 9.2b,f 60.5b,f Ramucirumab (14) IgG1 mAb VEGFR-2 III 2nd line Ramucirumab 283 9.2 0.87 (0.72–1.05), 0.14 2.8 0.63 (0.52–0.75), <0.0001 7.1 56.2 Placebo 282 7.6 2.1 0.7 45.7 Ramucirumab (15) IgG1 mAb VEGFR-2 III 2nd line; only patients Ramucirumab 197 8.5 0.71 (0.53–0.95), 0.0199 2.8 0.45 (0.34–0.60), <0.0001 4.6 60 with baseline AFP Placebo 95 7.3 1.6 1.1 39 400 ng/mL Cabozantinib (16) TKI c-Met, VEGFR-2, c-Kit, III 2nd line or 3rd line Cabozantinib 470 10.2 0.76 (0.63–0.92), 0.0049 5.2 0.44 (0.36–0.52), 0.001 4 64 RET, FLT-3, TIE2, Axl Placebo 237 8.0 1.9 0.4 33 Abbreviations: AFP, a-fetoprotein; CI, confidence interval; DCR, disease control rate; FGFR(1–4), fibroblast growth factor receptor; HR, hazard ratio; mAb, monoclonal antibody; mOS, median overall survival; mos, months; mPFS, median progression-free survival; N, number of subjects; ns, not significant; NR, not reported; ORR, objective response rate; PDGFR(-a,-b), platelet-derived growth factor receptors; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR(1–3), vascular endothelial growth factor receptor. aDisease-control rate was the percentage of patients who had a best-response rating of complete or partial response or stable disease that was maintained for at least 28 days after the first demonstration of that rating on independent radiologic review. bResponse based on modified RECIST criteria. cDefined as patients with complete response, partial response, or stable disease maintained for 6 weeks. dDefined as patients with complete response, partial response, or stable disease maintained for 12 weeks. eTime to progression. Clinical Cancer Research fPosthoc analysis of response using RECIST v1.1 ORR: 18.8% versus 6.5%; DCR: 72.8% versus 59.0%. Published OnlineFirst October 1, 2018; DOI: 10.1158/1078-0432.CCR-18-1254 Role of Angiogenesis in HCC (Table 1). Despite an initial breakthrough for the field, survival Cross-talk between FGF-2 and VEGF-A during initial phases of benefits observed with tyrosine kinase inhibitors (TKI) such as tumor growth induces neovascularization and further tumor sorafenib have been modest. Strategies for overcoming the high growth (33). FGF-2 and VEGF-A are associated with increased rate of acquired resistance to sorafenib, targeting other elements of capillarized sinusoids in HCC tumor angiogenesis (34), and angiogenic pathways alone or with other novel therapies, and the FGF stimulation modulates integrin expression that regulates investigation of biomarkers that may predict the efficacy of these endothelial cells in the microenvironment, thus altering cellular therapies are under development.