Targeted Therapy For Metastatic Cancer

  • Sungbeen Lee BSc Neuroscience and Physiology, University of Toronto

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Introduction

What is metastasis?

Metastasis, also known as secondary cancer, happens when cancer cells spread from the area where they initially formed to a different part of the body. Metastasis is the primary cause of death for more than 90% of patients with cancer.1

What is targeted therapy?

Targeted therapy is a type of cancer treatment that targets specific proteins that regulate cancer cell growth, division and spread. 

Significance of targeted therapy in metastatic cancer treatment

In recent years, there has been a major shift from the use of traditional broad-spectrum cytotoxic drugs to targeted drugs in mainstream cancer treatment.2 Compared to traditional chemotherapy drugs, targeted drugs can differentiate cancer cells from normal cells. This allows targeted drugs to offer their relatively low toxicity whilst having high potency.2

How is metastatic cancer diagnosed?

Based on the patient’s symptoms, healthcare providers offer investigation processes to patients such as:3

  • Clinical history examination
  • Physical examination
  • Magnetic resonance imaging (MRI)
  • Imaging studies such as computerised tomography (CT) and X-rays
  • Biopsy

What are the types of targeted therapies?

Monoclonal antibodies

Antibodies, found naturally in our blood, play a crucial role in the immune system by identifying foreign antigens, neutralising them, and triggering an additional immune system.4 Monoclonal antibodies are synthesised in laboratories to mimic natural antibodies. They recognise and target specific proteins on the surface of cancer cells.

Monoclonal antibodies directly target tumour cells whilst promoting a long-lasting anti-tumour immune response.4 Also, their specificity for tumour antigens makes them a useful candidate for delivering cytotoxic compounds directly to tumour cells to cause their death.4 They are now a primary component of cancer treatment, in addition to surgery, radiotherapy and chemotherapy.4

Examples of monoclonal antibodies used in cancer therapy

  • Trastuzumab
  • Cetuximab
  • Bevacizumab
  • Obinutuzumab
  • Nivolumab

Cancer growth blockers

Cancer growth blockers inhibit the action of growth factors, which provokes cancer cells to divide and grow. Growth factors are secreted molecules that regulate cell growth, division and differentiation. Growth factors then bind to cell surface receptors that set off a cascade of signalling events, resulting in a change in gene expression.14

Examples of cancer growth blockers include

  • Tyrosine kinase inhibitors such as axitinib (Inlyta)
  • mTOR inhibitors such as temsirolimus (Torisel)
  • BRAF inhibitors such as vemurafenib (Zelboraf)
  • MEK inhibitors such as trametinib (Mekinist)
  • Hedgehog pathway blockers such as vismodegib (Erivedge)
  • PI3K inhibitors such as idelalisib (Zydelig)
  • Proteasome inhibitors such as bortezomib (Velcade)
  • Histone deacetylase inhibitors such as vorinostat

Anti-angiogenic

Angiogenesis encourages tumour growth and metastasis by providing tumours with more oxygen and nutrients by forming new blood vessels. Anti-angiogenics block angiogenesis by interfering in different steps of tumour growth, thus slowing down tumour cell growth.6

Most of the approved anti-angiogenics target the actions of vascular endothelial growth factor (VEGF), which is an important growth factor for vascular endothelial cells that is up-regulated in many tumours.7 Anti-angiogenic therapy has been shown to reduce angiogenesis and render cancer cells more susceptible to immunotherapy due to its immunosuppressive properties.6

Examples of anti-angiogenic

  • Bevacizumab (Avastin)
  • Aflibercept
  • Ramucirumab
  • Sunitinib
  • Sorafenib
  • Axitinib

Poly (ADP-ribose) polymerase (PARP) inhibitors

PARP is a nuclear enzyme that is involved in DNA repair when it becomes damaged. The fact that certain tumours have defective homologous recombination mechanisms makes PARP particularly important for tumour cell survival by repairing damaged DNA.8 Moreover, PARP is observed to be upregulated in certain cancers such as triple-negative breast cancer (TNBC) and those with BRCA1 gene mutations.8 PARP inhibitors can make tumours more susceptible to DNA-damaging agents.PARP inhibitors in combination with chemotherapy or radiotherapy are seen as a promising therapeutic strategy.8

Examples of PARP inhibitors include

  • Olaparib (Lynparza)
  • Talazoparib (Talzenna)
  • Rucaparib (Rubraca)
  • Niraparib (Zejula)

Antihormonal therapy

Anti-hormonal therapy is a well-documented and well-studied method of cancer treatment.13 As a common treatment method for breast cancer, it works by inhibiting oestrogen production or by inhibiting the action of oestrogen that is required for cancer cell growth.13 This type of therapy is widely used because one-third of breast cancers in post-menopausal women have tested positive for the oestrogen receptor (ER), which is the required molecular target for this particular treatment.13

Examples of antihormonal drugs

  • Tamoxifen
  • Toremifene (fareston)
  • Fulvestrant (Faslodex)

The role of biomarkers in guiding targeted therapy

Depending on the type of cancer you have, healthcare providers determine whether a biomarker test is required to select a suitable cancer treatment. In most cases, targeted therapies require specific biomarkers to be present to work.10

In some cases, a biopsy may need to be taken for biomarker testing. The risks of taking a biopsy vary between different types of tumours and will be explained to you by your doctor.10 

How is targeted therapy delivered?

  • Oral administration as pills or capsules
  • Intravenous (IV) injection

What are the limitations of targeted therapy?

Although targeted therapies can deliver positive results in some cases, it is not without its limitations. Drug resistance and low treatment response rates remain a challenging issue because of the many mechanisms in which it can develop, such as drug efflux, epigenetic molecular modifications and DNA replication fork stabilisation.9 2

For example, although first and second-generation tyrosine kinase inhibitors (TKIs) for chronic myeloid leukaemia have resulted in an overall survival rate of 82%-95%, approximately 20% to 30% of the patients eventually experience resistance towards the treatment.5 For anti-angiogenics, drug resistance may be promoted due to the reduction of drugs delivered to the tumour through the bloodstream.6

In addition, the precise molecular mechanisms underlying metastasis are yet to be better understood, which can also aid the development of new treatment approaches to improve treatment efficacy.4 Sometimes, combination treatment of targeted therapy with chemotherapy or radiotherapy for cancer can produce more favourable outcomes. However, it often results in higher toxicity.9

What are the possible side effects?

Common side effects include:10

  • Diarrhoea
  • Liver damage such as death of liver cells, impairment in bile formation or flow and cirrhosis

Other possible side effects include

  • High blood pressure
  • Issues with blood coagulation and wound repair
  • Fatigue
  • Mouth ulcers
  • Skin reactions such as irritated and dry skin
  • Nail changes
  • Hair changes

Very rare side effects include gastrointestinal (GI) perforation, which is associated with the use of bevacizumab, sunitinib and sorafenib.1011

Emerging technologies in targeted therapy

Recent technological breakthroughs have enabled the lower cost of genetic testing and enhanced the speed and accuracy of genome sequencing. Major research endeavours conducted by The Cancer Genome Atlas, the International Cancer Genome Consortium have yielded a thorough genome profile of many types of cancers.13 This aids both the identification of targets within individual patients and investigations into the mechanisms underlying drug resistance.12

Moreover, the development of personalised cancer treatment is of significant interest due to its promising potential for better treatment effectiveness and lower side effects.12 The rapid developments in artificial intelligence, machine learning and digital pathology also have the potential to make the design process of a personalised cancer treatment easier.12

FAQs

What factors affect the success rate of targeted therapy?

The success rate of targeted therapy depends on many factors, including the type of cancer, the stage of cancer, the physical or mental condition of the patient before treatment, the dosage, and the type of targeted therapy given. 

How is cancer treatment progress monitored?

Patients receiving cancer treatment undergo regular check-ups. The healthcare provider will also conduct physical exams and medical tests including blood tests and imaging tests.

How to prepare for cancer treatment?

For better treatment outcomes and long-term health, it is recommended that patients eat a varied and balanced diet, exercise regularly and care for their mental health. 

Conclusion

Targeted therapy is one of the main treatment methods for metastatic cancer, which is the primary cause of death for more than 90% of cancer patients. By targeting specific molecular targets, targeted therapy can differentiate between cancerous and normal cells to prevent metastasis. It is a promising alternative to traditional chemotherapy which has relatively low toxicity and high potency.

There are many types of targeted therapies, which can be categorised according to the drug targets. The types of targeted therapies include monoclonal antibodies, cancer growth blockers, anti-angiogenics, poly (ADP-ribose) polymerase (PARP) inhibitors and antihormonal therapy. Following the identification of specific targets via biomarker tests in individual patients, a suitable type of targeted therapy is chosen and can be delivered orally or intravenously.

Despite the success of targeted therapy, drug resistance, drug toxicity, and low treatment response rates remain a major challenge. However, further research efforts into the molecular mechanisms underlying metastasis and the development of personalised treatment outcomes have the potential to better the treatment outcomes.

References

  1. Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther [Internet]. 2020 Mar 12 [cited 2024 Jun 21];5:28. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067809/
  2. Zhong L, Li Y, Xiong L, Wang W, Wu M, Yuan T, et al. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Sig Transduct Target Ther [Internet]. 2021 May 31 [cited 2024 Jun 21];6(1):1–48. Available from: https://www.nature.com/articles/s41392-021-00572-w
  3. Diagnosis. In: Diagnosis and Management of Metastatic Malignant Disease of Unknown Primary Origin [Internet]. National Collaborating Centre for Cancer (UK); 2010 [cited 2024 Jun 21]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK82142/
  4. Zahavi D, Weiner L. Monoclonal antibodies in cancer therapy. Antibodies (Basel) [Internet]. 2020 Jul 20 [cited 2024 Jun 21];9(3):34. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551545/
  5. Sun J, Hu R, Han M, Tan Y, Xie M, Gao S, et al. Mechanisms underlying therapeutic resistance of tyrosine kinase inhibitors in chronic myeloid leukaemia. Int J Biol Sci [Internet]. 2024 Jan 1 [cited 2024 Jun 21];20(1):175–81. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10750272/
  6. Lopes-Coelho F, Martins F, Pereira SA, Serpa J. Anti-angiogenic therapy: current challenges and future perspectives. Int J Mol Sci [Internet]. 2021 Apr 5 [cited 2024 Jun 21];22(7):3765. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038573/
  7. Duffy AM, Bouchier-Hayes DJ, Harmey JH. Vascular endothelial growth factor (VEGF) and its role in non-endothelial cells: autocrine signalling by VEGF. In: Madame Curie Bioscience Database [Internet] [Internet]. Landes Bioscience; 2013 [cited 2024 Jun 21]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6482/
  8. Morales JC, Li L, Fattah FJ, Dong Y, Bey EA, Patel M, et al. Review of poly (ADP-ribose) polymerase (Parp) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr [Internet]. 2014 [cited 2024 Jun 21];24(1):15–28. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806654/
  9. Giudice E, Gentile M, Salutari V, Ricci C, Musacchio L, Carbone MV, et al. Parp inhibitors resistance: mechanisms and perspectives. Cancers [Internet]. 2022 Mar [cited 2024 Jun 21];14(6). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945953/
  10. Targeted therapy for cancer - nci [Internet]. 2014 [cited 2024 Jun 21]. Available from: https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies
  11. Thornton E, Howard SA, Jagannathan J, Krajewski KM, Shinagare AB, O’Regan K, et al. Imaging features of bowel toxicities in the setting of molecular targeted therapies in cancer patients. Br J Radiol [Internet]. 2012 Oct [cited 2024 Jun 21];85(1018):1420–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474016/
  12. Barot S, Patel H, Yadav A, Ban I. Recent advancement in targeted therapy and role of emerging technologies to treat cancer. Med Oncol [Internet]. 2023 Oct 7 [cited 2024 Jun 21];40(11):324. Available from: https://doi.org/10.1007/s12032-023-02184-6
  13. Røsland GV, Engelsen AST. Novel points of attack for targeted cancer therapy. Basic Clin Pharmacol Toxicol [Internet]. 2015 Jan [cited 2024 Jun 21];116(1):9–18. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309509/

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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