Targeted Therapy

Targeted therapies are intended to target only the cancer cells while limiting damage to the surrounding normal cells. Conventional cancer therapies are unable to distinguish between cancerous cells and healthy cells. These side effects can be severe, significantly reducing the patient’s quality of life and compromising their ability to continue with treatment. The intention of targeted therapies is to increase the effectiveness of cancer therapy and reduce the negative side effects often associated with whole-body treatments such as chemotherapy and radiation therapy.

Targeted cancer therapies interfere with cancer cell division (proliferation) and spread in different ways. Many of these therapies focus on proteins that are involved in cell signaling pathways, which form a complex communication system that governs basic cellular functions and activities, such as cell division, cell movement, cell responses to specific external stimuli, and even cell death. By blocking signals that tell cancer cells to grow and divide uncontrollably, targeted cancer therapies can help stop cancer progression and may induce cancer cell death through a process known as apoptosis. Other targeted therapies can cause cancer cell death directly, by specifically inducing apoptosis, or indirectly, by stimulating the immune system to recognize and destroy cancer cells and/or by delivering toxic substances directly to the cancer cells.

Once a target has been identified, a therapy must be developed. Most targeted therapies are either small-molecule drugs or monoclonal antibodies. Small-molecule drugs are typically able todiffuse into cells and can act on targets that are found inside the cell. Most monoclonal antibodies usually cannot penetrate the cell’s plasma membrane and are directed against targets that are outside cells or on the cell surface.

Candidates for small-molecule drugs are usually identified in studies known as drug screens—laboratory tests that look at the effects of thousands of test compounds on a specific target, such as Bcr-Abl. The best candidates are then chemically modified to produce numerous closely related versions, and these are tested to identify the most effective and specific drugs.

Monoclonal antibodies, by contrast, are prepared first by immunizing animals (typically mice) with purified target molecules. The immunized animals will make many different types of antibodiesagainst the target. Next, spleen cells, each of which makes only one type of antibody, are collected from the immunized animals and fused with myeloma cells. Cloning of these fusion cells results in cultures of cells that produce large amounts of a single type of antibody, or a monoclonal antibody. These antibodies are then tested to find the ones that react best with the target.

Before they can be used in humans, monoclonal antibodies are “humanized” by replacing as much of the nonhuman portion of the antibody as possible with human portions. This is done through genetic engineering. Humanizing is necessary to prevent the human immune system from recognizing the monoclonal antibody as “foreign” and destroying it before it has a chance to interact with and inactivate its target molecule.

Targeted cancer therapies give doctors a better way to tailor cancer treatment, especially when a target is present in some but not all tumors of a particular type, as is the case for HER-2. Eventually, treatments may be individualized based on the unique set of molecular targets produced by the patient’s tumor. Targeted cancer therapies also hold the promise of being more selective for cancer cells than normal cells, thus harming fewer normal cells, reducing side effects, and improving quality of life.

Nevertheless, targeted therapies have some limitations. Chief among these is the potential for cells to develop resistance to them. In some patients who have developed resistance to imatinib, for example, a mutation in the BCR-ABL gene has arisen that changes the shape of the protein so that it no longer binds this drug as well. In most cases, another targeted therapy that could overcome this resistance is not available. It is for this reason that targeted therapies may work best in combination, either with other targeted therapies or with more traditional therapies.

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