**Emerging Targeted Therapies for Treatment of Hepatocellular Carcinoma (HCC) Hepatocellular Carcinoma (HCC)**

**Emerging Targeted Therapies for Treatment of** 

DOI: 10.5772/intechopen.71480

Sarwat Fatima, Nikki Pui-Yue Lee, Hiu Yee Kwan and Zhao Xiang Bian Zhao Xiang Bian Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Sarwat Fatima, Nikki Pui-Yue Lee, Hiu Yee Kwan and

http://dx.doi.org/10.5772/intechopen.71480

#### **Abstract**

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172 Hepatocellular Carcinoma - Advances in Diagnosis and Treatment

Cancer Biology & Therapy. 2011;**11**(5):450-456

DOI: 10.1080/02656730902976807

**25**(5):3295-3301

Hepatocellular carcinoma (HCC) has dismal diagnosis due to the presence of underlying cirrhosis, late diagnosis, and limited treatment options. Surgery or liver transplantation is restricted to those with small tumours or well-compensated liver diseases. Despite advances in early screening and diagnosis of HCC, survival of patients has not improved greatly. Furthermore, treatment options for advanced HCC are restricted to best supportive care. Currently, sorafenib is the only drug approved for the treatment of advanced HCC patients as well as for those not suitable for transarterial chemoembolization (TACE). Therefore, there is an urgent need to develop new agents for treatment. Hepatocarcinogenesis is a complex multistep process that involves deregulation of various signalling pathways. Thus, there is no dominant molecular mechanism in HCC and understanding of these pathways provides an opportunity for development of potential therapeutic agents in an effort to reverse, prevent or delay tumourigenesis. This review will summarise the significance of these pathways in HCC and discuss the therapeutic benefits or drawbacks of the potential target agents against these pathways especially those that have been part of clinical trials.

**Keywords:** hepatocellular carcinoma, targeted therapy, sorafenib, signalling pathways, immunotherapeutics

### **1. Introduction**

Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver cancer and is the second biggest cause of cancer-related deaths world-wide. The incidence of HCC is increasing all over the world but the highest rates of HCC are reported in South-East Asia with the leading rate of mortality occurring in China [1]. The risk factors for HCC are well

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

defined, such as hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcohol consumption, and non-alcoholic steatohepatitis (NASH) [2].

US Food and Drug Administration (FDA) for treatment and although it improves survival compared to placebo in clinical trials it suffers from adverse side-effects and high costs [8]. Unfortunately, with a majority of patients still diagnosed at late stage and with clinical phase III trials failing to improve survival benefits in intermediate and/or advanced HCC, new molecular therapeutics are urgently needed to address the dismal prognosis of HCC. One approach is to identify molecular targets from the several signalling pathways that are dysregulated in HCC. Several phase III trials have been completed to identify potential molecular

Emerging Targeted Therapies for Treatment of Hepatocellular Carcinoma (HCC)

http://dx.doi.org/10.5772/intechopen.71480

175

**2. Vascular endothelial growth factor (VEGF) receptor signalling**

Angiogenesis is a critical step for tumour growth and metastasis. With HCC being a highly vascular tumour, controlling tumour-associated angiogenesis offers a promising approach to

VEGF is the most well documented growth factor in angiogenesis. It exerts its effect by binding to its receptors, VEGF receptor 1 (VEGF-R1), VEGF-R2, and VEGF-R3, present on endothelial cells. VEGF secreted by tumour cells bind to its receptors and results in activation of signal transduction pathways promoting cell migration, proliferation, and survival of cancer cells leading to angiogenesis. VEGF overexpression is possibly induced by the hypoxic tumour environment, activation by epidermal growth factor (EGF) receptor (EGFR) and cyloonxygenase-2 signalling. Increased levels of VEGF, VEGFRs have been reported in HCC cell lines, tissue and serum of HCC patients. High levels of VEGF in HCC patients has been associated to poor OS and disease-free survival [9], vascular invasion [10] and portal vein emboli [11]. Additionally, Guo et al. [12] and colleagues reported poor prognosis for HCC patients with increased serum VEGF following TACE. VEGF is also more commonly expressed in HCV-associated HCC than in HBV-associated HCC providing clinical implications for different population of HCCs.

Other growth factors stimulating angiogenesis include fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR). Overexpression of either of these growth factors has also been associated to poor survival. There are four types of FGFRs

Sorafenib is currently the only drug approved for treatment of advanced HCC patients who cannot undergo TACE treatment. It is an orally active anti-angiogenic multi-kinase inhibitor. Several clinical studies have reported promising results. In the randomised phase III SHARP trial (ClinicalTrials.gov number NCT00105443), 400 mg of sorafenib twice daily, significantly increased the OS of advanced HCC patients (7.9 months *versus* 10.7 months) and the time to progression (TTP) (2.8 months *versus* 5.5 months) compared to the placebo group [8]. Similarly in another phase III Asia Pacific trial (NCT00492752), sorafenib increased the OS and TTP from 4.2 months to 6.5 months and from 1.4 months to 2.8 months, respectively [15]. The difference in the OS and TTP results in both studies could be due to patient HCC aetiology. The Asia Pacific trail had more HBV-associated HCC compared to the SHARP trial

(FGFR1, 2, 3, 4) and the PDGFR consist of PDGFRα and PDGFRβ [13, 14].

targets in HCC (**Table 1**).

inhibiting tumour progression.

(73% *versus* 12%).

The main reasons for the high rate of mortality are lack of diagnostic methods and limited treatment options for patients with advanced HCC. Surveillance programmes to identify patients with early HCC, such as by ultrasound sound screening and by serum alpha fetoprotein (AFP) levels, are not well implemented. Additionally, AFP levels are also dysregulated in benign liver diseases [3]. Some of the treatment options for HCC patients include surgical resection, liver transplantation (LTx), radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and sorafenib. Surgery has a 5-year survival rate of 70% but unfortunately at the time of diagnosis, only 10–30% of patients are suitable for this option. The biggest risk post-surgery is that of recurrence. The 5-year recurrence rate in patients with early HCC is about 68% after surgery [4]. LTx is suggested to HCC patients with tumours within the Milan criteria (a single lesion ≤5 cm, or up to three lesions ≤3 cm each) and is associated with a 5-year overall survival (OS) rate of 75%. However, the limitation of LTx is shortage of organ donation [5]. RFA is another option for patients with early HCC (<3 cm) and its survival benefits are comparable to those with surgical resection. However, high costs of RFA and complications involving peritoneal bleeding hinder its use [6]. TACE is the standard of care for intermediate HCC with preserved liver function, and with no signs of macrovascular invasion or extrahepatic spread. It has reported a median survival of 34 months and a survival benefit at 1, 3, 5 and 7 year as 82%, 47%, 26% and 16%, respectively. However, TACE is a heterogeneous operating technique with variation in efficacy depending on the choice of chemotherapeutic agents used [7]. For advanced HCC patients, sorafenib is the only drug approved by the



**Table 1.** Phase III clinical trials of molecular targets in HCC.

US Food and Drug Administration (FDA) for treatment and although it improves survival compared to placebo in clinical trials it suffers from adverse side-effects and high costs [8]. Unfortunately, with a majority of patients still diagnosed at late stage and with clinical phase III trials failing to improve survival benefits in intermediate and/or advanced HCC, new molecular therapeutics are urgently needed to address the dismal prognosis of HCC. One approach is to identify molecular targets from the several signalling pathways that are dysregulated in HCC. Several phase III trials have been completed to identify potential molecular targets in HCC (**Table 1**).
