Treatment for cancer used to be chemotherapy, however, the word chemotherapy has a lot of questions behind it with the concern of side effects, since it works on cancer cells as well as normal cells. But normal cells have the capacity to overcome side effects with the gain at the end of the day of getting rid of cancer.
With the introduction of targeted therapy, treatment became more directive toward cancer cells and, by the same token, side effects became overall less.
Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.
Because scientists call these specific molecules “molecular targets”, therapies that interfere with them are sometimes called “molecularly targeted drugs”, “molecularly targeted therapies”, or other similar names.
Targeted cancer therapies that have been approved for use in specific cancers include drugs that interfere with cell growth signaling or tumor blood vessel development, that promote the specific death of cancer cells, that stimulate the immune system to destroy specific cancer cells, and that deliver toxic drugs to cancer cells.
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, how a cell responds 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 to them.
The development of targeted therapies, therefore, requires the identification of good targets – that is, targets that are known to play a key role in cancer cell growth and survival. (It is for this reason that targeted therapies are often referred to as the product of “rational drug design”.)
For example, most cases of chronic myeloid leukemia (CML) are caused by the formation of a gene called BCR-ABL. This gene is formed when pieces of chromosome 9 and chromosome 22 break off and trade places. One of the changed chromosomes resulting from this switch contains part of the ABL gene from chromosome 9 coupled, or fused, to part of the BCR gene from chromosome 22. The protein normally produced by the ABL geneplays an important controlling cell proliferation and usually must interact with other signaling molecules to be active. However, Abl signaling is always active in the protein (Bcr-Abl) produced by the BCR-ABL fusion gene without interaction with other signaling molecules. This activity promotes the continuous proliferation of CML cells.
Therefore, Bcr-Abl represents a good molecule to target.
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 to diffuse 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 antibodies against 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 molecule 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.
The first molecular target for targeted cancer therapy was the cellular receptor for the female sex hormone estrogen, which many breast cancers require for growth. When estrogen binds to the estrogen receptor (ER) inside cells, the resulting hormone-receptor complex activates the expression of specific genes, including genes involved in cell growth and proliferation. Research has shown that interfering with estrogen’s ability to stimulate the growth of breast cancer cells that have these receptors (ER-positive breast cancer cells) is an effective treatment approach.
Several drugs that interfere with estrogen binding to the ER have been approved by the FDA for the treatment of ER-positive breast cancer. Drugs called selective estrogen receptor modulators (SERMs), including tamoxifen and toremifene (Fareston®), bind to the ER and prevent estrogen binding. Another drug, fulvestrant (Faslodex®), binds to the ER and promotes its destruction, thereby reducing ER levels inside cells.
Another class of targeted drugs that interfere with estrogen’s ability to promote the growth of ER-positive breast cancers is called aromatase inhibitors (AIs). The enzyme aromatase is necessary to produce estrogen in the body. Blocking the activity of aromatase lowers estrogen levels and inhibits the growth of cancers that need estrogen to grow. AIs are used mostly in women who have reached menopause because the ovaries of premenopausal women can produce enough aromatase to override the inhibition. Three AIs have been approved by the FDA for the treatment of ER-positive breast cancer: Anastrozole (Arimidex®), exemestane (Aromasin®), and letrozole (Femara®).
We’ll discuss more in upcoming weeks.