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Targeted and Biological Therapies

Targeted and Biologic Cancer Therapies

The conventional therapies used to treat cancers that we are all familiar with such as radiation, chemotherapy, and surgery, have served us well in our battle against the disease. But they are not without significant side effects. Healthy surrounding tissues, and even parts of our bodies remote from the area of the cancer can be affected by these treatments. Ideally science would like to find methods of treatment that are more specific to killing just the cancer cells and not affecting healthy tissues at the same time. As we learn more about the mechanisms by which our cells operate, the means by which they replicate, become malignant, or even just their methods of obtaining the nutrients that allow them to survive, we are finding that using these paths of normal cellular activity, we may be able to stop the growth of, or even kill, very specific cells such as those that have become cancerous. This is what targeted therapies endeavor to accomplish. These very specific methods which interfere with some aspect of cellular life without harming healthy cells in the process are referred to as targeted therapies. They interfere with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth. Because these biological molecules are called “molecular targets,” these therapies are sometimes called “molecular-targeted drugs,” “molecularly targeted therapies,” “targeted drug therapy”, or other similar names. By altering molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than current treatments and less harmful to normal cells. Their use is relatively new, and new discoveries are emerging at a rapid pace.

Cellular changes that lead to cancer

In order to understand how targeted and biologic therapies work, a very basic understanding of the cancer process is necessary. Cells grow and divide to form new cells as the body needs them. As cells grow old, they die, and new cells take their place. This process of normal, programmed cell death and replacement is called apoptosis. Occasionally, this orderly process goes wrong. Cells form when the body does not need them, and old cells do not die when they should. Extra cells can form a mass of tissue (a group or layer of cells that work together to perform a similar function) called a growth or tumor. Cells in cancerous tumors are not normal and divide uncontrollably, invading and damaging nearby tissues and organs. In addition, cancer cells can metastasize or break away from a malignant tumor and spread to other parts of the body. Under normal conditions, cell growth and division are mainly under the control of an arrangement of chemical and molecular signals that give instructions to cells. Changes or genetic alterations can disrupt the signaling process so that cells no longer grow and divide in a normal fashion, or no longer die when they are supposed to. Contributing to the cancer process are alterations in two types of genes. Proto-oncogenes are normal genes that are involved in cell growth and division. Changes, or mutations in these genes lead to the development of oncogenes which can promote or allow excessive and continuous cell growth and division. Tumor suppressor genes are normal genes that slow down cell growth and division. When a tumor suppressor gene does not work properly, cells may be unable to stop growing and dividing, leading to tumor growth.

Genetic changes that are not corrected by the cell can also lead to the production of abnormal proteins. Normally, proteins interact with each other as a kind of relay team to carry out the work of the cell. For example, when molecules called growth factors (GFs) attach themselves to corresponding growth factor receptors (GFRs) on the surface of the cell, a process carried out by proteins signals the cell to divide. Damaged proteins may not respond to these normal signals, over-respond to normal signals, or otherwise fail to carry out their normal functions. When these failures or errors occur, cancer develops causing it to reproduce excessively and allowing that cell to live longer than normal cells. As cancer cells continue to reproduce, their daughter cells also contain the cancer as well.

The immune system and its components

The immune system is a complex network of cells and organs that work together to defend the body against attacks by “foreign” or “non-self” invaders. This network is one of the body’s main defenses against infection and disease. The immune system works against diseases, including cancer, in a variety of ways. For example, the immune system may recognize the difference between healthy cells and abnormal cells (including cancer cells) in the body and works to eliminate these cells. However, the immune system does not always recognize cancer cells as foreign or abnormal. Also, cancer may develop when the immune system breaks down or does not function adequately. As we age there is a normal decline in the effectiveness of our immune systems, and they become increasingly incompetent with age. Biological therapies are designed to repair, stimulate, or enhance the immune system’s responses. (More about the immune system…)

Mechanisms of targeted cancer therapies

Targeted cancer therapies interfere with cancer cell growth and division in different ways and at various points during the development, growth, and spread of cancer. Many of these therapies focus on proteins that are involved in the signaling process. By blocking the signals that tell cancer cells to grow and divide uncontrollably, targeted cancer therapies can help to stop the growth and division of cancer cells.

Targeted cancer therapies include several types of drugs. Some examples are listed below, but many novel new drugs are currently in clinical trials and may be introduced in the near future. “Small-molecule” drugs block specific enzymes and GFRs involved in cancer cell growth. These drugs are also called signal-transduction inhibitors. Think of a small receptor site on the outside of a cell, that is designed to have a signal protein attach to it, which when attached, signals the cell to duplicate. If a drug is able to block that receptor site on the surface of a cancerous cell, when the signal protein comes to tell it to replicate it will not be able to deliver the message. This effectively stops that cancer cell from duplicating into additional malignant cells. “Apoptosis-inducing drugs” cause cancer cells to undergo apoptosis (normal programmed cell death) by interfering with proteins involved in the process. When the gene which controls this process is altered, the cell becomes immortal. These types of drugs turn that cell death function back on so that apoptosis will take place, allowing the cancerous cell to die. “Angiogenesis inhibitors” may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of blood vessels from surrounding tissue to a solid tumor, essentially starving it to death and preventing it from creating new pathways to spread through the circulatory system to other parts of the body.

Biological therapies for cancer

Biological therapy (sometimes called immunotherapy, biotherapy, or biological response modifier therapy) is a relatively new addition to the family of cancer treatments. Biological therapies use the body’s immune system, either directly or indirectly, to fight cancer or to lessen the side effects that may be caused by some cancer treatments.

Biological response modifiers, and how can they be used to treat cancer

Some antibodies, cytokines, and other immune system substances can be produced in the laboratory for use in cancer treatment. These substances are often called biological response modifiers (BRMs). They alter the interaction between the body’s immune defenses and cancer cells to boost, direct, or restore the body’s ability to fight the disease. BRMs include interferons, interleukins, colony-stimulating factors, monoclonal antibodies, vaccines, gene therapy, and nonspecific immunomodulating agents. They work by many different mechanisms:

  • Stop, control, or suppress processes that permit cancer growth
  • Make cancer cells more recognizable and, therefore, more susceptible to destruction by the immune system.
  • Boost the killing power of immune system cells, such as T cells, NK cells, and macrophages.
  • Alter the growth patterns of cancer cells to promote behavior like that of healthy cells.
  • Block or reverse the process that changes a normal cell or a pre-cancerous cell into a cancerous cell.
  • Enhance the body’s ability to repair or replace normal cells damaged or destroyed by other forms of cancer treatment, such as chemotherapy or radiation.
  • Prevent cancer cells from spreading to other parts of the body.

Cancer vaccines

Cancer vaccines are a form of biological therapy currently under study. Vaccines for infectious diseases, such as measles, mumps, and tetanus, are injected into a person before the disease develops. These vaccines are effective because they expose the body’s immune cells to weakened forms of the disease antigens that are present on the surface of the infectious agent. This exposure causes the immune system to increase production of plasma cells that make antibodies specific to that particular infectious agent. The immune system also increases production of T cells, which are designed to destroy abnormal cells. This small amount of disease antigen that was introduced via the vaccine, programs them on what to look for, and makes it possible for the T cells to recognize the infectious agent. Now activated and programmed, the next time the agent enters the body, the immune system is already prepared to respond and stop the infection.

Gene therapy

Gene therapy is an experimental treatment that involves introducing genetic material into a person’s cells to fight disease. Researchers are studying gene therapy methods that can improve a patient’s immune response to cancer. For example, a gene may be inserted into an immune system cell to enhance its ability to recognize and attack cancer cells. In another approach, scientists inject cancer cells with genes that cause the cancer cells to produce cytokines and stimulate the immune system. A number of clinical trials are currently studying gene therapy and its potential application to the biological treatment of cancer.

Cancer Immunotherapy

Cancer Immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating the patient's immune system to attack the malignant tumor cells that are responsible for the disease. This can be either through immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs, in which case the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies.

Since the immune system responds to the environmental factors it encounters on the basis of discrimination between self and non-self, many kinds of tumor cells that arise as a result of the onset of cancer are more or less tolerated by the patient's own immune system since the tumor cells are essentially the patient's own cells that are growing, dividing and spreading without proper regulatory control.

Other kinds of tumor cells display cell surface receptors that are rare or absent on the surfaces of healthy cells, and which are responsible for activating cellular signal transduction pathways that cause the unregulated growth and division of the tumor cell. Examples include ErbB2, a constitutively active cell surface receptor that is produced at abnormally high levels on the surface of breast cancer tumor cells.

Monoclonal antibody therapy

Antibodies are a key component of the adaptive immune response, playing a central role in both in the recognition of foreign antigens and the stimulation of an immune response to them. It is not surprising therefore, that many immunotherapeutic approaches involve the use of antibodies. The advent of monoclonal antibody technology has made it possible to raise antibodies against specific antigens such as the unusual antigens that are presented on the surfaces of tumors.

Tumor growth factors and targeted therapy

Researchers have discovered naturally occurring substances in the body that promote cell growth. These hormone-like substances are called growth factors. Growth factors activate cells by attaching to their specific receptors, which are present on the outer surface of the cells. Some cancer cells grow especially fast because they contain more growth factor receptors than normal cells do. One of the growth factors that have been linked to oral and oropharyngeal cancers is called epidermal growth factor or EGF. Oral and oropharyngeal cancers with too many EGF receptors tend to be especially aggressive. New drugs that specifically target and block EGF receptors have been tested in clinical trials. These drugs work by preventing EGF from causing cancer cells to grow and divide or by reducing the efficiency of cancer cells to repair injury to their DNA.

A drug called cetuximab (Erbitux) which blocks the growth receptor, has been successful in shrinking and eliminating oral cancers when it was given along with radiation. It has recently been approved by the Food and Drug Administration (FDA) to use along with radiation in people with advanced oral cancer. Most doctors have used chemotherapy along with the radiation. It isn’t known whether using cetuximab along with radiation is better, and that is still under investigation. Since the FDA approval for this drug was granted for head and neck use in 2006, we may see this drug used in other combinations as an adjunct to conventional chemotherapy and radiation or in combination with other drugs in the future. Cetuximab is also used alone (a mono-therapy) in people with widespread cancer that can’t be treated with radiation and no longer respond to chemotherapy. This drug is given intravenously and can cause rash, fever and chills and nausea. Another drug called erlotinib (Tarceva), also blocks the growth receptor. This drug, which is given as a pill, seems to have helped some patients with oral cancer. Further studies with this class of agents are being undertaken.

Targeted and biological therapies - side effects

Like other forms of cancer treatment, biological therapies can cause a number of side effects, which can vary widely from agent to agent, and patient to patient. Rashes or swelling may develop at the site where the biological response modifiers (BRM's) are injected. Several BRM's, including interferons and interleukins, may cause flu-like symptoms including fever, chills, nausea, vomiting, and appetite loss. Fatigue is another common side effect of some BRMs. Blood pressure may also be affected. The side effects of IL–2 can often be severe, depending on the dosage given. Patients need to be closely monitored during treatment with high doses of IL–2. Side effects of CSF's may include bone pain, fatigue, fever, and appetite loss. The side effects of MOABs (monoclonal antibodies) vary, and serious allergic reactions may occur. Cancer vaccines can cause muscle aches and fever.

The Potential impact of targeted and biological therapies

Targeted and biological cancer therapies may give doctors a better way to custom tailor cancer treatment for a specific patient. Eventually, treatments may even be individualized based on the unique set of molecular targets produced by an individual patient’s tumor biology. These cancer therapies also hold the promise of being more selective, thus harming fewer normal cells, reducing side effects, and improving the quality of life.

Connect the the National Cancer Institutes page on targeted therapies