03.02.5.2 Targeted Anti-Cancer Drugs

Targeted cancer medicines block the growth and spread of cancer by interfering with SPECIFIC molecules/cells involved in tumor growth and progression. Why is this important? Firstly, the drug maybe more effective, as it is will be preferentially killing the cancer cells. Secondly, the drug may have less severe side effects if it is not killing all the normal cells. Most importantly, it is possible that we can get a cure with some of the specific drugs.

One targeted approach is similar to a mechanism we have already discussed – enzyme inhibition. An activated enzyme, tyrosine kinase Bcr-Abl, underlies chronic myeloid leukemia. Thus, the obvious treatment for chronic myeloid leukemia is to inhibit the tyrosine kinase Bcr-Abl. This can be done with imatinib (Gleevec). With imatinib, the response rate is about 70%, which means they get better, and if these subjects continue to take imatinib for several years, many are cured.

Unfortunately, despite being developed to target an enzyme associated with the cancer, it does not mean that it is specific for that enzyme. Thus, adverse effects do occur with imatinib, and these include gastrointestinal (pain, diarrhoea, nausea), fatigue, headache, and cardiotoxicity.

Another approach to targeted anti-cancer drugs is monoclonal antibodies. Monoclonal antibodies are similar to the endogenous antibodies produced by the body’s immune system to fight off bacteria and viruses. They are made to specifically target and block a substance in the body or a specific cell type e.g. something specific to the cancer. Usually, monoclonal antibodies are designed to recognise a specific protein on the surface of a cell (Figure 3.28).

Figure 3.28 Monoclonal antibody (Copyright QUT, Sheila Doggrell)

Trastuzumab is a monoclonal antibody to the HER2/neu receptor that is overexpressed in some breast cancer. HER2 receptor overexpression leads to the rapid growth of breast cancer cells. Trastuzumab improves survival in late-stage/metastatic HER2-positive breast cancers, but it does also have side effects. Thus, trastuzumab is contraindicated in subjects with heart failure, and cardiac dysfunction is a major problem with the use of trastuzumab.

Tumours need to have blood vessels in them to survive i.e. all cells need oxygen and nutrients delivered by blood vessels to function. Vascular Endothelial Growth Factor A (VEGF-A) is required for blood vessel growth in tumours. Bevacizumab is a monoclonal antibody to VEGF-A which is used to prevent blood vessels developing in cancerous tumours. Bevacizumab is used in the treatment of colorectal, breast, renal, and non-small cell lung cancers, especially in metastases. Many of the common adverse effects are cardiovascular and may be related to inhibiting blood vessel growth as it will inhibit the growth of all blood vessels, not just those in tumours.