Knowing in detail the specific molecules that are involved in tumour growth and progression makes it possible to design new drugs or to screen for existing compounds that will interfere with the molecules’ function, thus blocking the growth and spread of cancer. Those molecules are described as “targets,” and the drugs that neutralize them are known as targeted therapies. Because targeted drugs attack only the molecules responsible for specific tumour cell behaviour, they are less toxic to normal cells compared with traditional chemotherapeutic agents. As a result, for certain types of cancer, targeted therapies have superseded older drugs and become the standard of care.

Refinements in scientists’ understanding of cancer and of methods of drug design and screening have led to the production of a significant number of targeted therapies. The majority of those agents are monoclonal antibodies and small-molecule drugs. Monoclonal antibodies are directed against targets on the surface of tumour cells. Because naturally occurring antitumour antibodies are present in exceedingly low quantities in the human body, to be harnessed therapeutically, large numbers of clones of the desired antibody must be generated by using animals (such as rabbits and mice). The animal antibody proteins are then isolated and “humanized” (animal portions of the antibodies are replaced by human components) through genetic engineering. Engineering is necessary in order to avoid rejection of the protein by the human immune system.

Small-molecule drugs (defined by their low molecular weight, typically less than 500 daltons) act on targets that are inside the cell. They are identified through screening processes that involve testing thousands of chemical compounds for their effects on a specific target. When an effect is detected, the compound is modified in different ways to optimize its activity and specificity.

Targeted therapies allow oncologists to treat the specific defects found in a patient’s tumour, which may be different from those found in the same tumour type in a different individual. Because of this, targeted therapies embody the concept of personalized medicine. However, similar to chemotherapeutic drugs, they suffer from the potential emergence of tumour-cell resistance. In many instances, resistance is due to mutations in the target molecule that disable the interaction of the drug with its target. To minimize this risk, targeted therapies are used in combination with one another or with conventional chemotherapeutic agents.

One of the first targeted therapies approved for use in patients was the monoclonal antibody trastuzumab (Herceptin), which is directed against the estrogen receptor and used to treat breast cancer. It was known that when estrogen occupied its receptor on the surface of breast cancer cells, it stimulated their growth. Occupying the receptor with an ineffective molecule, in this case trastuzumab, suppressed the growth stimulus. Several varieties of drug have since been developed to achieve that same effect. Another way to approach the suppression of breast cancer is by decreasing the presence of estrogen in the patient’s body. This can be accomplished by inhibition of an enzyme known as aromatase, which produces estrogen in the body. Thus, aromatase inhibition leads to decreased estrogen levels and slows the growth of estrogen-dependent cancers.

The drug imatinib is another example of a targeted therapy. By inhibiting an abnormal protein present only in chronic myelogenous leukemia (CML) cells, imatinib can control CML without causing extensive disturbance in normal cells. Gastrointestinal stromal tumours (GISTs), which are unrelated to CML and originate from a different cell type, possess a mutated protein with a similar function to the one targeted by imatinib and thus are also amenable to treatment with the drug.

Other targeted therapies have been developed that block other growth factor receptors or enzymes within cancer cells. Additional small-molecule targets include oncoproteins that are crucial for the maintenance of tumours, including the epidermal growth factor receptor and the substances Kit, BRAF, Her2/neu, and ALK.

Angiogenesis inhibitors

Since the progression of tumours requires the development of capillaries (a process known as angiogenesis) that supply tumour cells with oxygen and nutrients, interfering with this essential step is a promising therapeutic approach. Antiangiogenic drugs have been shown in animal studies to shrink tumours by destroying the capillaries that surround them and by preventing the production of new vessels. An angiogenesis inhibitor called bevacizumab (Avastin) was approved by the U.S. Food and Drug Administration in 2004 for the treatment of metastatic colorectal cancer. Bevacizumab works by binding to and inhibiting the action of vascular endothelial growth factor (VEGF), which normally stimulates angiogenesis. However, bevacizumab is not effective when administered alone and therefore is given in combination with traditional chemotherapeutic agents used to treat colorectal cancer, such as 5-fluorouracil (5-FU) and irinotecan. Angiogenesis inhibitors remain an object of intensive research.