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All anticancer drugs target tumors in some way. Most conventional treatments, however, attack healthy cells as well as cancer cells. As a result, there can be serious side effects from the treatment. A new approach to cancer treatment may help reduce side effects. The new treatment is called molecularly targeted therapy. It takes a more direct aim at cancer cells. And that means less damage to healthy cells.
Targeted therapies are designed to recognize a specific molecular change in a cancer cell that drives the growth and spread of a tumor. By zeroing in on its molecular target, these new medications destroy or slow the growth of cancer cells while avoiding normal, healthy cells. And because healthy tissues are spared, targeted therapies tend to bring about fewer and less severe side effects than conventional treatments.
Trillions of cells make up the normal, healthy body. Cells grow and divide in a controlled manner according to a complex system of chemical signals within the cells. These signaling pathways tell cells when to divide, when to be at rest, and even when to die. Such signals help each tissue and organ in the body maintain its proper shape and function.
If a problem arises in a cell's signaling system, it can push a healthy cell toward becoming a cancerous one. Usually, more than one signal has to go haywire for a tumor to arise. But over time, if a number of critical molecular changes accumulate, the healthy cell is transformed into a cancer cell.
Scientists have identified many molecular mistakes that lead to cancer. Defects in genes are a very common molecular change seen in cancer. Genes are microscopic pieces of DNA located within cells. The role of genes is to provide cells with instructions for producing proteins. Damaged genes make flawed proteins. Many proteins are involved in signaling. So, flawed proteins disrupt the signaling pathways that are essential for a cell to function normally.
Identifying the exact mistakes that lead to cancer can help doctors and researchers know how to treat cancer. Once a critical flaw has been identified, researchers search for a medication that can interfere with an abnormal molecule or malfunctioning process. The drug's interference in the malfunctioning process can inhibit the cancer's progression or even eliminate the tumor.
Some targeted therapies home in on tumors by seeking out molecules found only in cancer cells. Other targeted agents seek out molecules that are more abundant in cancer cells than in healthy cells. And still other treatments are focused on processes that are more important to the growth of cancer cells than normal cells.
There are two main classes of molecularly targeted agents under development: small molecule compounds and monoclonal antibodies.
Small molecule compounds are medications that either destroy cancer cells or stop their growth. Many of these drugs can be taken by mouth.
One example of a small molecule compound is Gleevec (imatinib). It's used to treat a rare stomach cancer called gastrointestinal stromal tumor (GIST) and certain types of leukemia.
Chronic myelogenous leukemia (CML) is an unusual type of cancer in that only one molecular defect is needed to turn a normal cell into a cancerous one. The abnormality arises when two genes fuse together and, as a result, produce an abnormal protein. This protein sends a signal to the cell that tells it to grow in an uncontrolled manner. Gleevec controls the growth of CML tumors by preventing the abnormal protein from signaling the cancer cells to grow.
Gleevec is also effective against other tumors that have defects in proteins similar to the one involved in CML.
Many other small molecularly targeted therapies are being created. Tarceva (erlotinib) was approved by the U.S. Food and Drug Administration (FDA) to treat metastatic non-small cell lung cancer and pancreatic cancer in certain circumstances or tumor types. Tarceva works by inhibiting a protein called the epidermal growth factor receptor (EGFR) from signaling the cell to grow. For this reason, it is classified as an EGFR inhibitor. EGFR is produced in excessive amounts by many tumors, such as those found in lung, breast, head and neck, pancreas, and colon cancer. However, tumors that have certain mutations in EGFR are most effectively treated with the drug erlotinib. In advanced stage lung cancer for example, EGFR mutated lung cancer is more effectively treated with erlotinib than with standard (nontargeted) chemotherapy. Whether a lung cancer has this EGFR mutation can be determined by a special molecular test performed on the patient’s tumor (biopsy). Because additional molecular defects give rise to these cancers, more than just one drug will likely be needed to effectively control or destroy these tumors.
The second category of targeted therapies is monoclonal antibodies. Antibodies are normal components of the immune system that help rid the body of foreign invaders or infectious agents such as bacteria. Antibodies are formed when they recognize abnormal surface patterns or antigens on the invader.
Antibodies trigger the body's immune response to an invader, and they are programmed to remember previous invaders so that they can effectively and quickly destroy them if they attack the body again.
Monoclonal antibodies are produced in a lab. They work in a similar way to the body's natural antibodies. They locate and bind to antigens found on cancer cells and eliminate them from the body. Monoclonal antibodies can be used alone to stimulate an immune response, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor.
Here are a few FDA-approved monoclonal antibody therapies:
Avastin (bevacizumab) has been approved by the FDA as first-line treatment for metastatic colorectal cancer, meaning the cancer has spread, as well as in the treatment of some other tumors including certain lung cancers, brain, and kidney cancers. It is the first drug to be approved that works by targeting angiogenesis, which is the formation of new blood vessels to the tumor.
Erbitux (cetuximab) has been approved for some cases of skin, head, neck, cancer and colorectal cancer. It is thought to work by targeting the epidermal growth factor receptor (EGFR) on the surface of cancer cells.
Herceptin (trastuzumab) is used to treat breast cancer. This monoclonal antibody targets a protein on breast cancer cells called the human epidermal growth factor receptor-2 (HER-2). Herceptin is only effective against breast tumors that overproduce the HER-2 protein. It has also been approved in the treatment of some gastric and gastroesophageal junction tumors.
Rituxan (rituximab) is used to treat B-cell non-Hodgkin lymphomas that carry a protein called CD20.
Zevalin (ibritumomab tiuxetan) binds to the same CD20 target that Rituxan does, so it's used to treat the same types of cancer as Rituxan. But Zevalin carries an additional punch because its monoclonal antibody is bound to a radioactive compound called yttrium-90, which can kill cancer cells. By delivering this damaging compound directly to the tumor, Zevalin allows larger and more deadly doses of the radioactive agent to reach the tumor while minimizing its damage to healthy cells.
Azerra (ofatumumab) is used for the treatment of chronic lymphocytic leukemia and is directed against the CD20 cell surface antigen.
Yervoy (ipilimumab) is used to treat people with advanced melanoma. It is directed against a T-lymphocyte-associated antigen-4 (CTLA-4), located on the surface of activated T cells.
In time, researchers envision being able to individualize cancer treatment for each person. By testing a person's tumor cells to determine the exact molecular abnormalities that are involved, the doctor would choose a combination of therapies to take specific aim at the major defects in the cells of the tumor.
Before this scenario is realized, existing targeted therapies must be refined, new targets and therapies must be identified, and the right combinations of agents must be devised. While science is only at the beginning of this revolutionary approach to cancer treatment, researchers are working toward making this vision a reality.
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