Overview

Bladder cancer occurs when abnormal tissue growth, known as a tumour, forms in the bladder lining and bladder muscles. In the UK, about 10,000 new cases of bladder cancer are reported per year. It is estimated that approximately 1 in every 130 females and 1 in every 55 males will develop bladder cancer at some point in their lifetime. 

Current standard treatments for bladder cancer are radiation therapy, chemotherapy, and surgery. However, in some cases, these treatments will not be effective, and they often come with challenges like severe side effects.¹ When these therapies are not effective, targeted therapy is a possibility. With targeted therapy for bladder cancer, certain proteins, enzymes, or other molecules particular to cancer cells are targeted in order to prevent their growth and spread. In this article, we will explore the available targeted therapies for combating bladder cancer.

What is targeted therapy?

As the name indicates, targeted therapy is a kind of cancer treatment that ‘targets’ the proteins that regulate the growth, division, and spread of cancer cells. Compared to conventional therapies like chemotherapy, targeted drugs utilised in targeted therapy function differently. They act by blocking the activity of particular enzymes, proteins, or other molecules involved in the development and spread of bladder cancer cells.

How is it different from traditional treatments?

The way in which chemotherapy and targeted treatment impact your body is one of their main distinctions. Chemotherapy can have several unfavourable side effects, such as tiredness, nausea, and hair loss, since it targets all rapidly developing cells, which might also include normal/healthy cells. However, in targeted treatment, these healthy cells are spared, and only cancer cells are targeted and destroyed. This accurate targeting results in fewer and milder side effects and is often simpler for patients to tolerate than chemotherapy. 

What are these targeted therapies, and how do they work?

There are different types of targeted therapies for bladder cancer; each is designed to work in specific ways depending on the characteristics of bladder cancer.

FGFR inhibitors

The proteins known as fibroblast growth factor receptors (FGFRs) aid in the development and multiplication of cells. However, sometimes mutations in the FGFR gene, which regulates the synthesis of these proteins, result in the uncontrolled growth and multiplication of bladder cells, resulting in cancer. In order to help slow down or inhibit the proliferation of these cancer cells with FGFR gene mutations, certain drugs known as FGFR inhibitors are used.

Erdafitinib

Erdafitinib is an FGFR inhibitor. This drug is used to treat advanced bladder cancer that has not responded to previous therapies, such as chemotherapy, and has specific changes in the FGFR3 gene.

EGFR inhibitors

Cancer drugs known as EGFR inhibitors target a protein on the surface of cancer cells called the epidermal growth factor receptor (EGFR). This protein is responsible for the division and growth of the bladder cancer cells. EGFR inhibitors target EGFR, thereby helping reduce or halt the development of cancer. Examples: erlotinib and gefitinib.²

Immune checkpoint inhibitors

These drugs act by helping your body’s immune system to recognise and attack bladder cancer cells. Your immune system's job is to recognise and eliminate abnormal cells, such as cancerous ones. However, cancer cells have evolved the means to "hide" from the immune system by utilising certain proteins as checkpoints, thereby preventing the immune system from destroying them. Checkpoint inhibitors work by blocking these proteins, allowing the immune system to better recognise and fight cancer cells.

PD-1/PD-L1 Pathway

The interaction between the proteins PD-1 (Programmed Death-1) on immune cells and PD-L1 (Programmed Death-Ligand 1) on cancer cells is one of the most frequent targets of immune checkpoint inhibitors in bladder cancer. Normally, the immune cell's PD-1 links to the cancer cell's PD-L1, telling it to leave the cancer cell alone and help it avoid discovery. Immune checkpoint inhibitors prevent this interaction, enabling the immune system to identify and combat the cancer.

Immune checkpoint

Inhibitors for bladder cancer are:

• Atezolizumab
• Pembrolizumab
• Durvalumab
• Nivolumab
• Avelumab³

Recent advances in targeted therapy

Antibody-drug conjugates

Antibody-drug conjugates (ADCs) are another type of targeted treatment. These drugs consist of a monoclonal antibody linked to a chemotherapy agent. An ADC is a lab-produced variant of an immune system protein that can identify and attach to a specific protein present on the surface of cancer cells. The ADC releases the linked chemotherapeutic drug inside the tumour once it is attached and absorbed into the cancer cell. This targeted approach allows the chemotherapy to kill cancer cells more efficiently while protecting most of the healthy cells in the body, thereby leading to fewer side effects compared to standard chemotherapy. Examples include vedotin enfortumab, and govitecan sacituzumab.^1,4 

VEGF/R targeted therapy

The vascular endothelial growth factor (VEGF) pathway is crucial for tumour growth in bladder cancer. Tumours utilise VEGF, a protein that stimulates angiogenesis (the development of new blood vessels to get oxygen and nutrients). VEGF enhances the blood supply to the tumour and promotes its development and spread by attaching to receptors on surrounding blood vessels and telling them to expand toward the tumour. By blocking the VEGF pathway, drugs such as bevacizumab attempt to effectively stop the tumour's blood flow and may even delay its growth.⁵

Drugs targeting the VEGF pathway for bladder cancer are:⁵

• Bevacizumab
• Ramucirumab
• Aflibercept
• Sorafenib
• Sunitinib
• Pazopanib

When is targeted therapy used?

When bladder cancer is metastatic—that is, when it has gone outside the bladder—or when conventional therapies like chemotherapy are ineffective, targeted therapy is typically advised. If tests reveal that your cancer has certain genetic alterations that can be targeted by targeted therapy, then it could also be a possibility. 

How to know if targeted therapy is right for you?

In order to examine the DNA of the cancer cells in your bladder, your doctor could advise genetic testing. If the findings indicate certain genetic changes, such as those in the FGFR gene, then you may benefit from targeted treatments. This, in turn, will improve your overall treatment effectiveness and quality of life. 

Challenges of targeted therapy

Even though this advanced treatment strategy is effective, it has certain limitations.

Not suitable for everyone

 Targeted therapy is only effective if your cancer has specific genetic mutations. If your tumour does not have these markers, targeted treatments may not work for you. 

Development of resistance

The possibility that cancer cells may eventually become resistant to targeted therapy presents another difficulty. Although targeted treatments may show promise in the short term, over time, some cancer cells may develop resistance to the therapy or find ways to evade it. 

Side effects

 Although targeted therapies generally cause fewer side effects than traditional chemotherapy, they can still lead to issues such as fatigue, skin problems, or high blood pressure, depending on the specific drug. For example, erdafitinib can cause a range of side effects, including mouth sores, fatigue, changes in kidney or liver function, diarrhoea, dry mouth, changes in nails, loss of appetite, altered taste, anaemia, dry skin and eyes, hair loss, and in some cases, more serious issues like hand-foot syndrome, constipation, belly pain, nausea, muscle pain, and eye problems. 

Limited availability

Access to targeted drugs may be more difficult in some situations since some are currently in clinical trials and may not be generally available for all patients.⁵

Summary

Bladder cancer occurs when abnormal tissue growth forms a tumour in the bladder lining. While common therapies like chemotherapy, radiation, and surgery are widely utilised, these can have serious side effects and may not always be beneficial. By targeting certain proteins or pathways that support the growth and metastasis of cancer cells, targeted treatment provides a more focused approach to treating bladder cancer. 

Widely explored targeted therapies include using FGFR inhibitors, which treat cancers with FGFR gene mutations. Another therapy is EGFR inhibitors to block proteins that aid in cancer cell division and immune checkpoint inhibitors to help the immune system recognise and destroy cancer cells. Antibody-drug conjugates (ADCs) that combine monoclonal antibodies with chemotherapy are also used to target cancer cells. VEGF inhibitors are another targeted treatment that prevents the formation of blood vessels that aid in the survival of tumours. However, these target therapies have some adverse effects, and not all patients can benefit from them since they depend on certain genetic alterations in the cancer. Moreover, since many of these targeted medications are still undergoing clinical studies, it may restrict patient access.