Cancer is a complex disease that needs a varied treatment approach. One of the most important recent developments is targeted therapy, which uses drugs to focus on specific molecules that cancer cells need to grow and spread. These therapies work in various ways to combat cancer, such as blocking signals that promote cancer cell growth and division, stopping the formation of blood vessels that feed tumours, delivering toxic substances to cancer cells, or depriving cancer cells of essential hormones. Some therapies enhance the immune system’s ability to destroy cancer cells, while others directly induce cancer cell death. Most targeted therapies consist of small-molecule drugs or monoclonal antibodies. They are also known as molecularly targeted therapies.¹ 

In contrast to chemotherapy and radiation, which impact both healthy and cancerous cells, targeted therapy focuses on blocking the signals that promote cancer cell growth and spread, aiming to minimise damage to normal cells as much as possible.²

In this article, we will understand the concept and process of targeted drug therapy and what to expect from targeted therapy.

How targeted therapy works

Targeted therapy focuses on specific molecules-targets, essential for cancer cell survival. These therapies interfere with the function of molecules, disrupting cancer’s ability to grow and spread. The primary targets can be proteins involved in cell signalling pathways, enzymes, or genetic mutations in cancer progression.

There are two targeted therapies:

1. Monoclonal antibodies - are proteins that bind to the specific antigen (proteins found on the surface of cancer cells). By attaching to these antigens, monoclonal antibodies can block the signal that promotes tumour cell growth or mark cancer cells for destruction by the immune system. 
2. Small molecular inhibitors - are drugs that can enter cells and interfere with the function of proteins or enzymes inside the cells. They inhibit cell signalling pathways that tell cancer cells to grow uncontrollably. Small molecule inhibitors are effective because they can target proteins involved in key cellular processes that are often mutated or overactive in cancer cells.³ 

Both types of targeted therapies are designed to interrupt cancer's ability to survive, often by blocking the signals that tell cancer cells to grow and divide, inhibiting the blood vessels that feed tumours, or marking the cancer cells for destruction by the immune system.

Examples of targeted therapy

Targeted therapies treat various cancers, especially those with specific genetic markers. Some key examples include: 

1. HER2 Inhibitors: These drugs focus on the HER2 protein, produced in excess in breast and other cancers. HER2 inhibitors, like pertuzumab and trastuzumab (Herceptin), prevent the HER2 protein from transmitting signals encouraging cancer cell growth.⁴
2. EGFR Inhibitors: These are for cancers with mutations in the epidermal growth factor receptor (EGFR) gene, such as certain lung cancers. EGFR inhibitors, like erlotinib (Tarceva), block signals from EGFR that drive cancer cell growth and division.⁴
3. BRAF Inhibitors: Employed in cancers like melanoma with mutations in the BRAF gene, drugs like vemurafenib (Zelboraf) target the mutated BRAF protein, which plays a role in cancer cell growth.⁴ 
4. PARP Inhibitors: Used in cancers with BRCA1 or BRCA2 mutations, such as some breast and ovarian cancers, PARP inhibitors like olaparib (Lynparza) inhibit an enzyme that cancer cells need to repair DNA, leading to cancer cell death. These therapies are tailored to cancers with specific molecular traits, making them highly effective for the appropriate patients.⁴
5. Angiogenesis inhibitors-These medications limits the blood supply to a tumour, slowing or halting its growth. They target specific proteins involved in developing new blood vessels and inhibit their function eg. bevacizumab.⁴
6. Anti-CD20 monoclonal antibodies- target the CD20 proteins in certain B-cell leukemias and non-Hodgkin lymphomas. Examples include rituximab and obinutuzumab.⁴
7. Tyrosine Kinase Inhibitors (TKIs): These drugs block proteins called tyrosine kinases, which send signals that trigger cancer cells to grow, multiply, and spread. By disrupting this signalling, the cancer cells may die. Examples include erlotinib, sunitinib, imatinib, and dasatinib.⁴
8. mTOR Inhibitors: These inhibitors target the mammalian target of rapamycin (mTOR), a protein that promotes cancer cell growth and spread. An example is Everolimus.⁴
9. CDK Inhibitors: Cyclin-dependent kinase (CDK) inhibitors block the signals from CDK proteins that promote cancer cell growth and division. Without these signals, the cancer cells may die. Examples include palbociclib, ribociclib, and abemaciclib.⁴ 

Who can benefit from targeted therapy?

Targeted therapy is an innovative cancer treatment that targets specific mutations within cancer cells. Over 80 targeted therapies treat various cancers, including:

1. Blood cancers: This includes cancers like leukaemia, multiple myeloma, and lymphoma.
2. Brain cancers: Cancers such as glioblastoma and neuroblastoma can be treated by drugs, including some that work as part of immunotherapy.
3. Bone and soft tissue cancers: Some soft tissue sarcomas are treated with targeted therapies.
4. Breast cancers: Targeted therapy is effective for certain types of breast cancer, including those with BRCA gene mutations, HER2-positive, hormone receptor-positive, and triple-negative breast cancer.
5. Digestive system cancers: These include cancers like colorectal cancer, esophageal cancer, gastrointestinal stromal tumour (GIST), neuroendocrine tumours, pancreatic cancer, stomach cancer, liver cancer, and gallbladder cancer.
6. Head and neck cancers: Treatment of laryngeal cancer, nasal cavity, nasopharyngeal cancer, oral cancer, and oropharyngeal cancer can be treated with targeted therapies.
7. Lung cancers: Both non-small cell lung cancer and small cell lung cancer, as well as mesothelioma, may be treated with targeted drugs.
8. Reproductive system cancers: This includes cervical cancer, high-risk or recurrent endometrial cancer, and prostate cancer.
9. Skin cancers: Melanoma and cutaneous squamous cell carcinoma are treatable with targeted therapy.
10. Thyroid cancers: Types like anaplastic, medullary, and papillary/follicular thyroid cancer respond to targeted therapy.
11. Urinary system cancers: Cancers like bladder cancer, kidney cancer, and prostate cancer are targeted with targeted therapies.

This approach allows for tailored treatments based on the specific characteristics of cancer, improving outcomes and offering more personalised care.³ 

Advantages of targeted therapy

Targeted therapy has transformed cancer treatment by providing more precise and effective options compared to traditional chemotherapy. Unlike chemotherapy, which harms both healthy and cancerous cells, targeted therapies specifically target the molecular and genetic changes that fuel cancer growth. This precision has improved outcomes for patients with previously hard-to-treat cancers, such as chronic myeloid leukaemia (CML), gastrointestinal stromal tumours (GISTs), and renal cell carcinoma, leading to long-term survival in many cases.

Targeted therapy impacts more common cancers such as breast, colorectal, lung, and head and neck cancers. By targeting specific molecules involved in tumour growth, these therapies have enhanced survival rates and reduced recurrence. The insights gained from chemotherapy have guided the development of targeted treatments, aiding physicians in managing side effects and improving patient outcomes. 

Additionally, targeted therapy has opened new avenues for research, encouraging collaboration across disciplines and enhancing the understanding of cancer biology. A new field of supportive care has developed to address the unique side effects of these treatments.⁵ 

Limitations and challenges

• Genetic Complexity: Most cancers have multiple genetic mutations, so predicting or treating all combinations is impossible. Single-target mutations, like Bcr-abl in chronic myeloid leukaemia, develop drug resistance over time.⁶ 
• Combination Therapy: To overcome the limitations of single-agent therapies, combinations with chemotherapy, radiotherapy, or other targeted therapies are often used. However, these combinations can increase toxicity risks.
• Toxicity in Trials: Clinical trials combining agents like sorafenib and bevacizumab or bevacizumab and pazopanib caused severe toxicity. Similar issues existed in trials with EGFR- and VEGF-targeting agents and immune checkpoint inhibitors.⁷ 
• Cross-reactivity: Cancer-specific targets can cross-react with healthy cells, leading to toxicities, such as gastrointestinal effects with EGFR inhibitors or cardiotoxicity with Her-2 treatments.⁸
• Immune-related Toxicities: Immune checkpoint inhibitors cause serious side effects like pneumonia, endocrinopathy, and myocarditis in some patients.⁹ 
• Administration Issues: Oral targeted therapies pose challenges for non-oncology specialists, who may struggle with managing drug toxicities in the context of overall cancer care.^5,10 

Common side effects

• Initially, targeted therapy was thought to have lower toxicity compared to traditional chemotherapy. However, researchers have since discovered that it can also cause significant side effects, on the therapy type and individual response. 
• Common side effects include diarrhoea, liver issues, elevated blood pressure, fatigue, mouth sores, changes in nails hair colour, and skin problems like rashes and dryness. Rarely, serious complications such as perforations in the oesophagus, stomach, or intestines can occur. 
• Fortunately, various medications are available to manage these side effects, either by preventing them or treating them as they arise. Most side effects generally resolve after the treatment ends.¹¹ 

How is targeted therapy administered?

Most small-molecule drugs are typically available in tablet or capsule form, while most monoclonal antibodies work intravenously. However, some monoclonal antibodies, like rituximab, can be given subcutaneously. When there are no contraindications, it shortens treatment times. Trastuzumab is also administered subcutaneously in remote areas, reducing travel and time away from home for patients.¹² 

Summary 

Targeted therapy represents a significant advancement in cancer treatment, offering a more precise approach that minimises harm to healthy cells while effectively disrupting cancer growth.  Targeted therapies focus on specific molecules essential for tumour progression, - such as monoclonal antibodies and small molecular inhibitors - and have improved outcomes for patients across various cancer types. Despite the challenges, including genetic complexity and potential toxicity from combinations with other treatments, the benefits of personalised care exist. As research continues to evolve, targeted therapy will play an increasingly vital role in the future of oncology, enhancing both efficacy and patient quality of life.