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Molecular Targeted Therapy of Hepatocellular Carcinoma

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Molecular Targeted Therapy of Hepatocellular Carcinoma Journal of Cancer Therapy, 2013, 4, 426-439 http://dx.doi.org/10.4236/jct.2013.42A052 Published Online February 2013 (http://www.scirp.org/journal/jct) Molecular Targeted Therapy of Hepatocellular Carcinoma Kimberly Terry1, Mehmet Sitki Copur2* 1University of Nebraska College of Pharmacy, Omaha, USA; 2Saint Francis Cancer Treatment Center, Grand Island, USA. Email: *[email protected] Received December 18th, 2012; revised January 19th, 2013; accepted January 28th, 2013 ABSTRACT Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related mortality worldwide. Despite decades of efforts by many investigators, systemic chemotherapy or hormonal therapy has notoriously failed to show an improvement in survival. With a median survival of 8 months, and 1- and 3-year survival rates of 20% and 5%, respectively, the effective treatment of HCC remains far from satisfactory. Better understanding of the pathogenesis of this disease, identification of molecular targets for therapeutic intervention and availability of promising molecularly targeted therapies may change this dismal picture. In this review we will focus on what is cur- rently known about the molecular pathogenesis of HCC, and explore the currently available and future molecular based therapies targeting these pathways. Future research in this area will maximize clinical benefit while minimizing the toxicity and cost through utilization of novel targeted agents. Keywords: Hepatocellular Carcinoma (HCC); Treatment; Molecular Therapies; Novel Agents 1. Introduction many other are at different stages of clinical development (Figure 2). While these targeted therapies may offer The fifth most common cancer worldwide and the third hope as main treatments for patients who are not amena- most common cause of cancer-related deaths globally, ble to undergo surgical resection or transplant, they can HCC poses a great challenge [1,2]. The incidence of constitute the basis for promising adjunctive therapies in HCC in the United States has almost doubled in recent combination with currently available treatment modali- decades [3]. Due to multiple etiologies leading to the ties. In this article we will review the pathways identified development of this disease, HCC patient populations are in the pathogenesis of HCC along with currently avail- very diverse. It can occur in various underlying settings able and in development therapies targeting these path- such as hepatitis B and C, nonalcoholic steatohepatitis, ways hemochromatosis, autoimmune hepatitis, alcohol-related liver disease, primary biliary cirrhosis, and primary scle- 2. Pathways and Targeted Therapeutic rosing cholangitis. Systemic therapy with various classes Agents in HCC of agents, including hormonal and cytotoxic agents, has provided little to no benefit. Improved understanding of 2.1. Vascular Endothelial Growth Factor, the mechanism of hepatocarcinogenesis, coupled with the Fibroblast Growth Factor, and Platelet Derived Growth Factor and Receptors discovery of a multitude of molecular pathways leading (VEGF/VEGFR, FGF/FGFR, PDGF/PDGFR) to the development of HCC, has created a great opportu- Pathway nity to identify new targets and effective therapies (Fig- ure 1). The initial demonstration of improved survival Hepatocellular carcinoma (HCC) is one of the most vas- benefit by sorafenib in advanced HCC has opened a new cular solid tumors. Vascular endothelial growth factor era of molecularly targeted therapies, resulting in the (VEGF) plays a critical role in mediating angiogenesis in discovery of a diverse spectrum of novel agents, many of HCC and is a potential therapeutic target. VEGF can which are currently under active clinical investigation function by inducing vascular promotion and growth on and development. Targeted agents that inhibit angio- several cell types varying from hepatocytes, hepatic stel- genesis, epidermal growth factor receptor, and mammal- late cells, endothelial progenitor cells to hemangiocytes. ian target of rapamycin, insulin-like growth factor and Thus blockade of VEGF-mediated pathways, either by anti-VEGF neutralizing antibody or tyrosine kinase in- *Corresponding author. hibitors distrupts carcinogenesis and angiogenesis [4]. In Copyright © 2013 SciRes. JCT Molecular Targeted Therapy of Hepatocellular Carcinoma 427 Figure 1. Altered signaling pathways in HCC. Figure 2. Molecularly targeted therapies in HCC. addition to VEGF, several other angiogenic factors in a meaningful improvement in the treatment of tis deadly HCC have recently been identified. These factors can disease in 2008 [10]. Since then several antiangiogenic also regulate angiogenic processes through interaction and other molecularly targeted agents have been and with VEGF or VEGF-independent pathways [5,6]. In- currently being evaluated in clinical trials of HCC (Table creased levels of vascular endothelial growth factor 1). (VEGF) and microvessel density have been shown to be associated with worsening survival in HCC [7-9]. A 2.1.1. Bevacizumab phase III clinical trial revealed that an anti-angiogenic Bevacizumab, a recombinant humanized monoclonal agent “sorafenib” extended overall survival in patients antibody that targets VEGF has been studied either as a with advanced HCC, as the first drug ever demonstrating single agent or in combination with cytotoxic or other Copyright © 2013 SciRes. JCT 428 Molecular Targeted Therapy of Hepatocellular Carcinoma Table 1. Molecular targets and therapeutic agents. gets VEGFR-1/flt-1, VEGFR-2/KDR, and VEGFR-3/Flt- 4, all VEGFR tyrosine kinases and PDGFR, and the c-kit Molecular Targets Therapeutic Agents [13,14]. This drug interferes with the ATP binding sites VEGF/VEGFR Sorafenib of VEGF receptors. In a phase I study vatalanib was well Bevacizumab tolerated and showed clinical activity in a variety of solid Vatalanib (PTK787) Cediranib (AZD2171) tumors. Administered once daily, at a dose of 750 mg to Brivanib 1250 mg in patients with unresectable HCC, no CR or Sunitinib PR was observed. Nine patients had stable disease, and Pazopanib (GW786034) nine had progressive disease [15]. Linifanib (ABT869) EFGF/EGFR Cetuximab 2.1.3. Cediranib (AZD2171) Erlotinib Gefitinib Cediranib (AZD2171) is a potent inhibitor of both Lapatinib VEGFR-1 and VEGFR-2. It also has activity against IGF/IGFR OSI-906 c-kit, PDGFR-β, and FLT4 at Nano molar concentrations BMS554417 [16]. Cediranib has been shown to inhibit VEGF signal- IMC-A12 ing. Cediranib was well tolerated up to 45 mg per day in AVE1642 BII022 patients with a broad range of solid tumors. The most common toxicities included diarrhea, dysphonia, and Ras/Raf/MEK/ERK Sorafenib hypertension. In a phase II study of cediranib in 28 pa- Regorafinib Selumetinib (AZD6244) tients with advanced HCC, 19 patients were evaluable for toxicity [17]. The main adverse events were fatigue, hy- PI3K/Akt/mTOR MK2206 AZD8055 pertension and anorexia. The primary objective of this Everolimus phase II study was to assess 6-month survival. Secondary Sirolimus objectives were to assess tumor response, time to pro- Temsirolimus gression (TTP), and toxicity. Twelve patients (42.9%) Wnt-β-catenin PFK118-310 survived 6 months, 15 (53.6%) died within 6 months, and PFK115-584 CGP049090 1 (3.6%) was lost to follow-up before 6 months. The me- dian OS was 5.8 months. No patients experienced a con- Hedgehog HPI-1 (NanoHHI) firmed response. The median time to progression (mTTP) MET Tivanitib was 2.8 months [18]. FGF Lenalidomide 2.1.4. Brivanib Brivanib alaninate is an investigational, oral, anti-tumor targeted agents. In a multicenter phase II study of 46 pa- agent that inhibits vascular endothelial growth factor tients with compensated liver disease and unresectable receptor (VEGFR) and fibroblast growth factor receptors HCC, bevacizumab led to a 13% partial response rate (FGFR). It has shown tumor growth inhibition in mouse (PR) with a median progression-free survival (PFS) of HCC xenograft models. A phase II study evaluated the 6.9 months and overall survival (OS) of 53% at 1 year, efficacy and safety of brivanib in patients with unre- 28% at 2 years, and 23% at 3 years. Bevacizumab was sectable, locally advanced, or metastatic HCC who had associated with significant reductions in tumor enhance- received either no prior systemic therapy or one prior ment by dynamic contrast-enhanced magnetic resonance regimen of angiogenesis inhibitor [19]. At 800 mg oral imaging and reductions in circulating VEGF-A and stro- daily dose brivanib provided a median OS of 10 months mal-derived factor-1 levels [11]. and TTP of 2.8 months with 5% PR and 47% disease Bevacizumab has also been studied in conjunction control rate in previously untreated HCC patients. Most with cytotoxic chemotherapy, gemcitabine and ox- frequently observed grade 3 - 4 adverse events included aliplatin (GEMOX) for the treatment of unresectable fatigue (16%), high levels of AST (19%), and hypona- HCC. In a phase II study of 33 patients with advanced tremia (41%). In a randomized phase III trial, BRISK-FL, metastatic HCC, treatment with combination regimen of brivanib versus sorafenib were evaluated in patients with bevacizumab and GEMOX resulted in a 20% response advanced HCC who had not received prior systemic rate (RR) with a median OS of 9.6 months. While there treatment. The study did not meet its primary overall were no patients with a complete response (CR), 27% survival objective based upon a non-inferiority statistical had stable disease [12]. design. 2.1.2. Vatalanib (PTK787) 2.1.5. Sunitinib Vatalanib (PTK787) an oral angiogenesis inhibitor, tar- Sunitinib, an oral multikinase inhibitor targeting VEGFR- Copyright © 2013 SciRes. JCT Molecular Targeted Therapy of Hepatocellular Carcinoma 429 1, VEGFR-2, also has inhibitory activities for other re- patients with advanced HCC, and 600 mg was chosen for ceptor tyrosine kinases including PDGFR-a/b, c-KIT, further development of pazopanib in advanced HCC. FLT3, and RET kinases [20]. In a study of 34 patients with advanced HCC, sunitinib was given 37.5 mg orally 2.1.7. Linifanib (ABT869) once daily on a 4-weeks-on, 2-weeks-off schedule (6 Linifanib (ABT869), a novel potent and selective inhibi- weeks per cycle).
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