Introduction 

Liver cancer is the 5th most common cancer in the world and one of the leading causes of cancer-related deaths. The most common types of liver cancer include hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma. HCC accounts for up to 90% of all primary liver cancers. In most cases, liver cancer is as a consequence of underlying liver dysfunction, such as cirrhosis. As a result, many patients are not diagnosed until the cancer has already reached an advanced stage, limiting the utility of curative treatment options like surgery or liver transplantation. Instead, treatment often involves targeted therapy, which aims to kill cancer cells whilst leaving healthy cells be.^1,2

Several studies have attempted to understand how liver cancer develops and progresses. Although treatment options depend on the stage, liver function and independent patient factors, the development of therapies against specific molecular pathways has revolutionised therapy for liver cancer. This article will explore some of these pathways and how targeted therapies exploit these changes in HCC.¹

What is targeted therapy?

Cancer is a process by which cells grow uncontrollably. Some cancers, like liver cancer, can also develop the ability to spread to surrounding tissues. This spread of cancer is called metastasis. Alongside uncontrolled cell division, cancer cells can also have the ability to evade cell-death signals, accumulate genetic mutations, and form new blood vessels (angiogenesis), allowing access to oxygen and nutrients.³ All of these mechanisms help cancer grow and spread.

Targeted therapy is a form of therapy that targets the proteins involved in cell growth, division and spread. Targeted therapy drugs are typically either small-molecule inhibitors or monoclonal antibodies, which can enter or attach to specific targets on cancer cells. The ways in which targeted therapy aims to treat cancer include:³

• Boost your immune system against cancer cells
• Stop cancer cells from growing uncontrollably 
• Stop signals involved in angiogenesis
• Deliver toxins, chemotherapy, or cytotoxic drugs that kill cancer cells
• Causes cancer cell death by triggering apoptosis (programmed cell death mechanism)

Key targets for therapy in HCC

Several targeted agents are under investigation for use against liver cancer, with most focusing on HCC. The most promising drugs are anti-angiogenic agents (i.e. drugs that prevent angiogenesis), which have been shown to significantly improve overall survival.¹

Key pathways involved in HCC

Raf/MEK/ERK

The Raf/MEK/ERK pathway controls cell growth, differentiation and survival. The pathway is triggered by a growth factor binding to a receptor protein on the surface of cells (specifically, a receptor tyrosine kinase). This binding triggers downstream signalling and leads to the activation of proteins that promote cell growth. In cancer cells, this pathway is constantly activated, leading to uncontrolled cell growth and division. This drives the progression of cancer.^1,4

PI3K/Akt/mTOR

The PI3K/Akt/mTOR pathway is involved in controlling cell growth, cell metabolism, cell survival and cell death. This pathway is abnormally or over-activated in 30-50% of HCC cases. Mutations can accumulate in different pathway members, leading to the pathway becoming overactive. This promotes tumour development and limits apoptosis - a form of programmed cell death that usually acts to kill cancer cells before they can divide.¹

Angiogenesis

HCC is associated with hypervascular tumors, meaning they have a large number of blood vessels running through or close to them. This additional blood (and oxygen) supply can promote cancer growth and metastasis. Angiogenesis (the production of new blood vessels) is controlled by growth factors and inhibitors. The most important growth factor involved in angiogenesis is vascular endothelial growth factor (VEGF). Mutations in VEGF, which promote vessel growth and cancer progression, are often detected in cirrhotic livers, making VEGF an effective target for targeted therapy.^1,5

Immune checkpoints

Although the immune system is vital for fending off infections, active immune cells can cause harmful inflammation. Immune checkpoints are one way in which the immune system keeps this inflammation under control. When the immune system is active, immune checkpoints become more active and “shut off” immune cells to prevent tissue damage. 

Many cancers, including HCC, produce these checkpoint proteins to hide themselves from the immune system and prevent it from attacking. One example is the programmed cell death ligand 1 (PD-L1), which binds to PD1 proteins on immune cells to stop them from attacking the tumour.^1,3

Small molecule inhibitors: kinase inhibitors 

Sorafenib

Sorafenib is a small-molecule drug that inhibits angiogenesis. It acts by inhibiting receptor tyrosine kinases such as VEGF and platelet-derived growth factor (PDGF). It also inhibits Raf/MEK/ERK-mediated signalling. It is currently used as a first-line therapy for unresected (cancer that has not been operated on) and advanced HCC, and it has been shown to improve overall survival. Furthermore, these drugs have shown favourable safety profiles, any most patients could complete their course of treatment. However, noted side effects include diarrhoea, fatigue and anorexia.^1,2,4,5

Lenvatinib

Lenvatinib is another multi-receptor tyrosine kinase inhibitor. It targets receptors including VEGF, fibroblast growth factor (FGF) and PDGF. Clinical studies have found that lenvatinib is more beneficial for progression-free survival (the time from treatment starting to the cancer spreading or progressing at all) compared to sorafenib, and it shows better activity against tumours. Alongside its satisfactory safety profile, this has led to its approval as a first-line treatment, alongside sorafenib, for unresectable HCC. Noted side effects include hypertension and decreased body weight.^1,2,5

Regorafenib

Regorafenib is another small molecule multi-kinase inhibitor, and is structurally similar to sorafenib. It was proposed as an alternative treatment for people who didn’t respond to sorafenib. Studies found that regorafenib improves overall survival time, and that it is comparably safe to lenvatinib and sorafenib. It has therefore been approved as a second-line treatment for HCC. Side effects included hypertension, fatigue and diarrhoea. ^1,2,5

Cabozantinib

Cabozantinib is reserved for people whose cancer 1) did not respond to curative treatments and 2) progressed whilst being treated with sorafenib. It is a multi-kinase inhibitor that targets several different receptors, including VEGF. Studies found that cabozantinib improves overall survival time compared to a placebo, with side effects including fatigue, reduced appetite and nausea. It has therefore been approved as second-line therapy for unresectable HCC for those previously treated with sorafenib.^1,2,5

Monoclonal antibodies 

In the context of cancer treatment, monoclonal antibodies are lab-produced proteins that specifically target and bind to certain proteins on the surface of cancer cells. These antibodies can be used for diagnosis, treatment, and research.

Pembrolizumab and nivolumab

Pembrolizumab is an anti-PD1 monoclonal antibody. It blocks PD1’s interactions with the immune checkpoint protein PD-L1, preventing immune cells from being deactivated and allowing them to kill the cancer cell. Studies have found that pembrolizumab is effective against HCC whilst remaining manageably safe. Furthermore, it offered greater overall survival and progression-free survival benefit in people previously treated with sorafenib. 

Nivolumab is another anti-PD1 antibody that has been approved as second-line treatment for HCC in people who had previously been treated with an anti-angiogenic drug or tyrosine kinase inhibitor.^1,2,5

Ramucirumab

Ramucirumab is a monoclonal antibody that inhibits the activation of VEGF receptor 2. Studies has shown that ramucirumab increases overall survival rates compared to a placebo. As such, it has been approved as single-agent therapy for people who have been previously treated with sorafenib. Known side effects include fatigue and abdominal pain.^1,2,5

Bevacizumab

Bevacizumab is a monoclonal antibody that targets VEGF and prevents its binding to its receptor. Studies studying bevacizumab both as a single agent and in combination with other therapies for unresectable HCC have shown it improves overall survival and progression-free survival.¹

Challenges and future directions 

Although targeted therapies have revolutionised treatment options for liver cancer,, challenges remain. HCC is an aggressive cancer that is normally diagnosed at an advanced stage, and clinical conditions and features can vary significantly between patients. Therefore, treatment decisions depend on the stage of the cancer, the patient’s liver function and individual factors, such as the presence of specific mutations. The presence and development of treatment resistance can further complicate treatment.^1,2

Future research on targeted therapy could focus on finding ways to predict a patient’s response to specific treatments in order to help identify those more likely to benefit from a drug. This would also limit toxicities in those who are unlikely to benefit.^1,2,5

Summary 

Liver cancer is one of the most common types of cancer in the world and a leading cause of cancer-related death. Targeted therapies use small molecule inhibitors or monoclonal antibodies to target pathways that may be dysregulated in cancer. These pathways are involved in angiogenesis (novel blood vessel formation), cell growth, differentiation, survival and death. Targeting angiogenesis may help prevent and/or reduce metastasis, whilst targeting immune checkpoints may boost the immune system’s ability to recognise and kill cancer cells. 

Sorafenib is frequently used as first-line therapy against HCC, followed by lenvatinib, regorafenib and cabozantinib. These drugs target signalling pathways by inhibiting proteins such as vascular endothelial growth factor (VEGF) receptors. Monoclonal antibodies such as pembrolizumab and nivolumab are used to activate the immune system, while ramucirumab and bevacizumab both act on VEGF receptors or VEGF itself. The future directions in this exciting field revolve around identifying biomarkers to predict the utility and suitability of these therapies in different individuals.