RLO: Pharmacogenomics

• Introduction
• Variation In Drug Responses
• Pharmacogenetic Variation
• Clinical Implications
• Pharmacogenetic Testing In Cancer
• The Future

Pharmacogenetic Testing In Cancer

Some of the most advanced applications of pharmacogenetic knowledge are those in the field of cancer therapeutics. Cancer is an unusual disease, as it arises through the accumulation of multiple mutations in certain genes within a cell, that together act to disrupt the normal checks and controls over cellular function and replication. This leads to uncontrolled and inappropriate cellular proliferation. Cancer cells therefore have distinct genetic profiles; increasing understanding of the molecular genetics of cancer is making it possible to exploit the differences between normal and cancerous cells to target therapeutics.

The major problem with conventional chemotherapy is that to achieve reasonable efficacy, a substantial degree of toxicity (and hence significant adverse side-effects) is required. Targeting drugs or other therapeutics more specifically to tumour cells both increases efficacy and reduces toxicity.

Herceptin
One of the best known examples of genetic targeting is that of Herceptin® (generic name trastuzumab). This is an antibody-based (biological) therapeutic used for the treatment of HER2 positive breast cancers, ie. those that produce abnormally high levels of human epidermal growth factor, ~20% of all breast cancers. Breast cancer cells that produce high levels of HER2, a cell surface molecule, are stimulated to replicate by the binding of HER2. Herceptin competitively binds to HER2, blocking growth factor binding and targeting the cancer cells for destruction by the body’s own systems. Non-cancerous cells do not produce large amounts of HER2 and are relatively unaffected, reducing the toxicity of the treatment. Purists might argue that the design of therapeutics such as Herceptin and Glivec® (generic name imatinib) do not represent true pharmacogenetics, because they are specifically targeted to the genetic nature of the tumour cells, as opposed to the patient’s genotype, but the commercial success of these agents has had a significant impact on the profile of pharmacogenetics as a tool for drug design and development.