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Advances in Targeted Therapies Tutorial

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NCI Highlights

Types of Targeted Therapies

In This Section:

Introduction

Before we begin to discuss how specific targeted therapies work, we will first review three types of drugs that can be used as targeted therapies—small molecules, antibodies, and vaccines. Each of these drug types has distinct characteristics that have important biological and clinical implications.

There are icons representing three types of targeted therapies. The first icon, labeled 'Small Molecules', shows three small purple oval shapes. The second icon, labeled 'Antibodies', shows a single purple 'Y-shape' with identical notches at the end of each of the upper arms of the 'Y'. The third icon, labeled 'Vaccines', shows a needle and syringe with a light-purple fluid in the syringe.

Small Molecules

Many targeted therapies are small molecules. Once in the body, most small molecules can easily travel across cell membranes, including the plasma membrane. This means that they can be used to interfere with proteins located either outside or inside the cell. Small molecules are often designed to interact with specific areas of the target protein in order to modify its enzyme activity or its interaction with other molecules.

Gleevec® (imatinib) is one example of a small-molecule targeted therapy that inhibits a few key signaling pathways.

This image shows a cross-section of a portion of a cancer cell, including the cell membrane, cytoplasm, and nucleus. Spanning the cell membrane are two receptors shaped like clubs. These receptors are interacting with each other and are glowing, indicating that they are active. A string of oval shapes representing proteins in a signaling pathway form a line from the bottom of the receptors to the nucleus. The first four ovals are glowing, indicating that they are active. A small purple targeted therapy molecule labeled Gleevec® is attached to the fifth oval in the pathway. This oval and all subsequent ovals are light gray indicating that Gleevec® has prevented activation of its target and all downstream molecules in the pathway.

Monoclonal Antibodies

The interaction of signaling molecules with receptors on the outside of a cell often activates pathways inside the cell. Monoclonal antibodies can interfere with these signaling pathways in cancer cells in a number of ways:

First, antibodies can work outside the cell by preventing signaling molecules and receptors from interacting with each other.

This image shows a cut-away of the surface and interior of a green cancer cell, including the cytoplasm and nucleus. There is a close up view of the cell surface showing two receptors separated by a short distance. A targeted therapy antibody, in the shape of a 'Y', is bound to one of the receptors. The antibody prevents the receptors from interacting and thus maintains them in an inactive state. The signaling pathway that extends from the receptor is also inactive.

Second, they can also be used as delivery vehicles, guiding radioactive molecules or toxins to the cancer cells.

This image shows the surface of a cancer cell. Embedded in the cell membrane is a large protein. Attached to the protein are two Y-shaped antibody molecules representing targeted therapies. The first antibody has a symbol for radioactivity attached, indicating a linked radioactive isotope. The second antibody molecule has a skull and cross-bones symbol attached, indicating a toxin is linked to the antibody.

Third, antibodies attached to a cell can trigger an immune response that destroys the cell.

This image shows a layer of normal cells with a mass of green cancer cells in the middle. In the middle of the image is an antibody icon. There are three blue immune cells near the cancer cells. The immune cells are active and releasing substances that act on the cancer cells. Two of the cancer cells are black, indicating that they have been killed by the immune response.

Herceptin® (trastuzumab), Avastin® (bevacizumab), Bexxar® (tositumomab), Mylotarg® (gemtuzumab), and Rituxan® (rituximab) are examples of monoclonal antibodies used to treat cancer.

More Information

Antibodies Are Effective Targeted Therapies

Antibodies have become an important form of targeted therapy over the past several years. Antibodies are used as targeted therapies because they can be engineered to interact with very specific targets. This high degree of specificity helps avoid the unwanted side effects that can occur if a therapy interferes with molecules other than the target.

Monoclonal antibodies can be very effective targeted therapies, but they are also associated with a number of challenges. Antibodies are large proteins that cannot easily cross cell membranes. Because of this, they are most often designed to recognize molecules that are outside the cell or on the cell surface.

Also, production of antibodies is very different from the chemical processes used to generate small molecules. Customized cell lines must be made to engineer antibodies that recognize a specific target. These antibodies must then be carefully purified to ensure that they are safe for patients.

Therapeutic Cancer Vaccines

The immune system is programmed to defend the body against invaders, such as a cold virus, but its ability to fight cancer is limited because it doesn't usually recognize cancer cells as foreign. In fact, some cancers actively suppress the body's immune responses.

This image shows the torso of a body. In the body the lymphatic system is shown and is labeled 'Immune System'.

Unlike other targeted therapies, therapeutic cancer vaccines do not act specifically on pathways in cancer cells. Instead, they act broadly by trying to activate the body's immune system to make it recognize and attack cancer cells.

This image shows the torso of a body with the internal organs visible. There is a green spot on the colon labeled 'Cancer'. A circle with a close-up view of the tumor is projecting from the colon. The close-up shows a mass of green cancer cells within a layer of pink normal cells. There are three blue cells on top of the cancer cells representing immune cells.

More Information

Cancer Vaccines Enhance Immune System Response

The use of cancer vaccines so far has almost uniformly focused on patients who are already undergoing treatment—so they are called therapeutic cancer vaccines. Through mechanisms that researchers are now beginning to understand, the immune system often fails to recognize cancer cells, and simply leaves them to potentially take root and form tumors.

Therapeutic cancer vaccines try to refresh the immune system's memory. The cancer vaccine may contain inactivated cancer cells, viruses that express tumor antigens (unique proteins or protein bits that sit on the surface of cancer cells and can trigger some immune response), or any antigens that are overexpressed by cancer cells.

Therapeutic cancer vaccines are often given with another agent—called an adjuvant—that enhances the immune response. One commonly used adjuvant is interleukin-2. This protein heightens the activity of the immune cells responsible for orchestrating an immediate immune response when an invader molecule is recognized. Other adjuvants include antigens not located on cancer cells but known to induce a strong general immune response. The idea is that if the immune system is very active, it will do a better job attacking all of its targets, including cancer cells.

Self Test

Questions

  1. Which of the following types of targeted therapies are usually given to patients orally?
    1. Small molecules
    2. Monoclonal antibodies
    3. Vaccines
    Check answer.

  2. Which types of therapies can cause the immune system to attack cancer cells?
    1. Small molecules
    2. Monoclonal antibodies
    3. Vaccines
    4. Both Monoclonal antibodies and Vaccines
    Check answer.

  3. Which types of therapies can be used to directly target molecules inside the cell?
    1. Small molecules
    2. Vaccines
    Check answer.

Answers

  1. Correct answer to Question 1: a
    1. Small molecules - Correct answer. Because of their chemical properties, small molecules can usually be given to patients orally.
    2. Monoclonal antibodies - Incorrect answer. Monoclonal antibodies are delivered by intravenous infusion. Antibodies and other protein therapies cannot be given orally because they would be broken down by the body before they could enter the circulation.
    3. Vaccines - Incorrect answer. Vaccines are usually administered by intramuscular, subcutaneous, or intravenous injection, although researchers are working to package vaccines in more stable ways in order to allow for oral delivery.

  2. Go to Question 2.
    Correct answer to Question 2: d
    1. Small molecules - Incorrect answer. Small molecules usually target cellular signaling pathways and do not induce an immune response.
    2. Monoclonal antibodies - There is a better answer. Monoclonal antibodies can cause the body's immune system to attack cancer cells, but they are not the only type of targeted therapy that can do this.
    3. Vaccines - There is a better answer. Vaccines do cause the body's immune system to attack cancer cells, but they are not the only type of targeted therapy that can do this.
    4. Both Monoclonal antibodies and Vaccines - Correct answer. Both monoclonal antibodies and vaccines can activate the immune system to attack cancer cells.

  3. Go to Question 3.
    Correct answer to Question 3: a
    1. Small molecules - Correct answer. Small molecules can cross the cell membrane to target molecules in the cell, but they are not the only type of targeted therapy that can do so.
    2. Vaccines - Incorrect answer. Vaccines activate the immune system to recognize molecules produced by cancer cells.