Types of Targeted Therapies
Cancer Cell Processes
Developing New Targeted Therapies
Summary and Conclusions
How are Targeted Therapies Linked to Personalized Medicine?
Targeted therapies are transforming the way people treat cancer. With help from molecular biology and genomic sequencing technologies, it is now possible to discover good therapeutic targets within cancer cells and then to design treatments that selectively interfere with them.
Targeted therapies have already begun to make personalized medicine a reality and will continue to help doctors tailor cancer treatment based on the characteristics of an individual's cancer. As many new types of targeted therapies become available, patients will need help deciding among them. Health care professionals should become familiar with the concept of targeted therapies so they can communicate with their patients about these new approaches and help them make better informed treatment decisions.
This tutorial is for oncology health professionals who wish to learn more about targeted therapies. Some of the questions that will be answered include:
- What are targeted therapies?
- What do these new treatments target?
- Which targeted cancer therapies are currently approved by the Food and Drug Administration (FDA)?
- How can I find clinical trials that are evaluating targeted therapies?
What Is Standard Chemotherapy?
Over the years, oncologists have prescribed what we now call standard chemotherapy because they found by trial and error that these drugs worked. They reduced the cancer burden in many of their patients, largely by killing rapidly dividing cells.
Standard chemotherapy often results in collateral damage to healthy tissue, causing unwanted side effects that impair the circulatory system, the immune system, the digestive system, and others. Only later did oncologists discover which molecules and processes are disrupted by standard chemotherapy. Because these traditional drugs usually affect processes that occur in all rapidly dividing cells, many normal cells throughout the body that are undergoing active growth and cell division can also be damaged.
How Are Targeted Therapies Different?
Unlike standard chemotherapy, targeted therapies are designed to interact with specific molecules that are part of the pathways and processes used by cancer cells to grow, divide, and spread throughout the body. Targets are chosen very carefully. When researchers discover a potentially vulnerable molecule involved in a cancer process or pathway, they validate it by doing more research, and then, if all goes well, they design new therapies to disrupt its activity with great precision.
Many targeted therapies are associated with fewer and less toxic side effects than standard chemotherapy or radiation because they cause little or no collateral damage to normal cells. This can contribute to the quality of life for patients undergoing treatment.
In summary, targeted therapies are different because:
- They act on specific molecular targets that have been identified through research, while most standard chemotherapies act on all rapidly dividing cells.
- They are deliberately chosen or designed to interact with their target, while many standard chemotherapies were identified through trial and error.
Also, targeted therapies may be associated with fewer and less toxic side effects than standard chemotherapy, since they may cause less damage to normal cells.
What Makes a Good Target?
The best target for therapy is a molecule or pathway that is present in cancer cells and absent in normal cells. This ensures that the therapy will only attack cancer cells.
Unfortunately, this is not usually the case. It is often difficult to find targets that are present only in cancer cells, in part, because cancer cells evolve from normal cells. The next best target for therapy is a molecule that is present more frequently in cancer cells compared to normal cells. In this case, it may be possible to adjust the dose of a drug so that cancer cells are killed more often than nearby normal cells.
Other possible targets for therapy include molecules that are present on both cancer cells and normal cells, but the patient's body can replace the normal cells that get destroyed.
Types of Targeted Therapies
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.
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.
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.
Third, antibodies attached to a cell can trigger an immune response that destroys the cell.
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.
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.
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.
- Which of the following types of targeted therapies are usually given to patients orally?
- Small molecules
- Monoclonal antibodies
- Which types of therapies can cause the immune system to attack cancer cells?
- Small molecules
- Monoclonal antibodies
- Both Monoclonal antibodies and Vaccines
- Which types of therapies can be used to directly target molecules inside the cell?
- Small molecules
- Correct answer to Question 1: a
- Small molecules - Correct answer. Because of their chemical properties, small molecules can usually be given to patients orally.
- 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.
- 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.
- Go to Question 2.
Correct answer to Question 2: d
- Small molecules - Incorrect answer. Small molecules usually target cellular signaling pathways and do not induce an immune response.
- 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.
- 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.
- Both Monoclonal antibodies and Vaccines - Correct answer. Both monoclonal antibodies and vaccines can activate the immune system to attack cancer cells.
- Go to Question 3.
Correct answer to Question 3: a
- 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.
- Vaccines - Incorrect answer. Vaccines activate the immune system to recognize molecules produced by cancer cells.
Cancer Cell Processes
Targeting Cancer Cell Processes
All cell processes—including growth, death, and differentiation—depend on the action of signaling molecules and pathways. A number of safeguards exist in normal cells to ensure that these processes are carried out correctly. But cancer cells employ mechanisms to bypass these safeguards so they can grow uncontrollably at the expense of normal cells and tissues. These mechanisms include increased signaling for cell growth, evasion of cell death, increased blood vessel formation, and invasion into surrounding tissues and metastasis.
In this section, we'll discuss how normal cells control their growth and explore some mechanisms used by cancer cells to bypass cellular safeguards. Examples of some therapies that target these sinister mechanisms will be presented.
In normal cells, growth, division, and differentiation are highly regulated processes. Some signaling molecules—called growth factors—promote cell division. Other signaling molecules cause cells to stop growing.
Many signaling molecules, including growth factors and growth inhibitors, bind to receptors on the surface of the cell. In many cases, these receptors must interact with one another, or dimerize, before they can become fully activated.
Once they are activated, receptors activate relay teams of proteins inside the cell—called signaling pathways. Activated signaling pathways carry messages from the receptor to the inside of the cell and sometimes all the way to the DNA in the nucleus.
Activation of these signaling pathways is often carried out by the transfer of chemicals, called phosphates, from one member of the relay team to the next. This process is known as phosphorylation. Receptors and other proteins that perform phosphorylation are called kinases.
The messages carried by the activated signaling pathways lead to the accumulation and activation of certain proteins that either promote or inhibit cell growth and division. The rate of cell growth and division depends on the balance of these two types of signals.
Unlike normal cells, cancer cells display uncontrolled growth control, so they can ignore signals to stop growing. Some cancer cells can make their own growth factors. These growth factors travel to the outside of the cell, where they interact with and activate the cancer cell's growth factor receptors.
Some cancer cells make more growth factor receptors than normal cells—this is called overexpression. Cancer cells with overexpressed growth receptors may be stimulated to grow when growth factors are present at levels that would be too low to stimulate growth of normal cells. This is because having more receptors available increases the chances that a growth factor will find its receptor.
Other cancer cells may have mutations in the genes that code for growth factor receptors. Some of these mutations result in the formation of dysfunctional receptors that remain in the "ON" position for growth even when no growth factor is present.
Cells can also bypass normal growth regulation by altering the way signals inside the cell operate. Increased levels of certain proteins in a pathway, or genetic mutations that alter these proteins, may cause the pathway to transmit growth signals on its own, with little or no regard for signals coming from nearby normal cells. Alternatively, other mutations may keep cells from receiving or transmitting signals that tell them to stop growing.
Targeted therapies can be designed to interfere with the renegade growth factor signaling of cancer cells. The goal is to block any part of a dysregulated growth signaling pathway from communicating with the other elements of the pathway.
For example, drugs that bind to a cancer cell's growth factor receptors can block the receptors from interacting with their growth factor or prevent them from dimerizing with other receptors.
Agents can also keep receptors in the "OFF" position or prevent them from transmitting a phosphorylation signal along the growth pathways within the cell.
Another strategy is to target the proteins that sit in relay teams and carry signals within the cell. The goal is to prevent them from transmitting the signal.
Drug Resistance and Targeted Therapies
Drug resistance is a serious problem for all cancer therapy. For targeted therapies, knowing the pathway that has been hit successfully before resistance developed, often helps researchers develop alternative molecules to again disrupt the cancer cells.
For example, resistance to the targeted drug Gleevec® (imatinib) is linked to mutations within the kinase domain of a protein called Bcr-abl. No novel pathways are involved. Using this knowledge, scientists have developed small molecule inhibitors that target this location. Dasatinib, also called Sprycel, developed by Bristol-Myers Squibb is a multi-targeted kinase inhibitor with higher affinity for the Bcr-abl kinase than imatinib. When patients who developed resistance to imatinib were given dasatinib, 93 percent of them again showed a response. Also, Novartis has developed a small-molecule kinase inhibitor called Tasigna (nilotinib) that can be given when a patient develops resistance to imatinib.
Example: Herceptin® (trastuzumab)
One example of a therapy designed to target a cell surface receptor is Herceptin® (trastuzumab). Herceptin® (trastuzumab) is a monoclonal antibody that interacts with a growth factor receptor called HER2. An excessive number of HER2 receptors are found in approximately 20% of breast cancers—and these cancers tend to be among the most aggressive types.
HER2 interacts—or dimerizes—with other receptors on the cell surface, activating signaling pathways that cause the cell to proliferate. One of the ways that Herceptin® (trastuzumab) works is by binding with HER2 and preventing it from interacting with other receptors on the cell surface. This keeps the receptor from activating the pathways that promote growth and division of breast cancer cells.
Herceptin® (trastuzumab) may also interfere with cancer cell growth by activating an immune response.
Herceptin® (trastuzumab) was initially approved by the FDA for the treatment of patients with HER-2 overexpressing metastatic breast tumors who had already received chemotherapy or who had not yet received chemotherapy and would be given Paclitaxel® along with Herceptin® (trastuzumab). More recently, Herceptin® (trastuzumab) has been approved for use as an adjuvant therapy in combination with doxorubicin, cyclophosphamide, and Paclitaxel® in women with earlier-stage HER2-positive disease. This approval was based on clinical trials that showed that women treated with this regimen had prolonged disease-free survival compared with women who received chemotherapy alone.
Example: Gleevec® (imatinib)
Gleevec® (imatinib) is a small molecule that blocks the signaling activity of certain proteins inside a cell. Proteins bound by Gleevec® (imatinib) cannot function in their relay team. They can no longer transmit phosphorylation signals along the pathways that lead to cell growth and division. Gleevec® (imatinib) can inhibit several different proteins, including two proteins involved in growth signaling.
Gleevec® (imatinib) was first developed for use in patients with chronic myelogenous leukemia, or CML. Gleevec® (imatinib) can inhibit several different proteins, including two proteins involved in growth signaling called abl and c-kit. Patients with CML have a mutant form of the abl protein known as Bcr-abl. Bcr-abl is stuck in the "ON" position and fuels cancer cell growth by phosphorylating other signaling pathway members. Gleevec® (imatinib) improves the chances of survival of CML patients. Gleevec® (imatinib) is also approved by the FDA for the treatment of unresectable or metastatic gastrointestinal stromal tumors that express a gene which makes another good Gleevec® (imatinib) target, the c-kit protein.
Normal Cell Death
We have shown that growth pathways and growth inhibition pathways regulate cell growth. Now we will look at another way normal cells control their growth. They use a process called apoptosis.
In adults, the number of body cells is kept relatively constant. Stressed, diseased, malfunctioning, or irreversibly damaged cells, as well as cells that need to be removed routinely as part of normal growth and development, are all removed by apoptosis, also called programmed cell death or cell suicide. Billions of adult cells die each day by apoptosis. These cells are then replaced by new, healthy cells. Within every cell there are signaling pathways that favor cell survival and others that favor apoptosis. The decision to undergo apoptosis depends on the balance of pro-apoptotic and pro-survival signaling pathways.
Signals that trigger apoptosis can come from outside or within the cell.
When the signal comes from the outside, a molecule released from a nearby cell binds to a surface receptor. This binding initiates pro-death signaling pathways within the cell. One signaling molecule, called TRAIL (TNF-related apoptosis-inducing ligand) can cause apoptosis when it binds to either Death Receptor 4 or Death Receptor 5.
Apoptosis can also be initiated from within a cell. Cells have a number of internal surveillance proteins that are constantly looking for signs of trouble, such as the presence of damaged DNA that cannot be repaired. If a serious problem is detected, pro-death signaling pathways are activated to begin the process of cell suicide.
Cells supervise their own self-destruction through a controlled series of steps. The process is highly regulated in order to minimize inflammation and harm to nearby cells.
The apoptotic cell shrinks and rounds itself up. Next, it condenses its DNA and cuts it into fragments. The cell eventually breaks into small vesicles that can be easily engulfed by immune cells called macrophages.
Cancer Cells Evade Cell Death
Normally, cells that begin to divide at the wrong time or with damaged DNA will undergo apoptosis. Cancer cells, however, develop a number of strategies to evade apoptosis. The ability to do this is critical to a cancer cell's survival. Avoiding apoptosis can also help cancer cells resist some therapies, such as radiation and conventional chemotherapy that work by inflicting enough cellular damage to prompt a call for apoptosis.
Cancer cells also often avoid apoptosis by altering the surveillance proteins that normally detect problems or induce apoptosis. Proteins that are responsible for these jobs can be rendered ineffective through mutation or by simply being produced at lower levels.
Some cancer cells evade apoptosis by overproducing anti-apoptotic proteins or creating mutant proteins that are better at blocking pro-apoptotic signals. For example, some cancer cells evade apoptosis by expressing high levels of the anti-apoptotic protein Bcl-2.
Targeted Therapies Promote Cell Death
The goal of therapies that target apoptosis is to tip the balance toward cell death for cancer cells.
Targeted therapies can be used in two different ways to promote apoptosis:
- Some therapies activate pro-apoptotic pathways, directly leading to cell death.
- Other therapies attempt to counter the overactive anti-death proteins present in cancer cells.
Although these therapies may cause cell death on their own, they are often used to prime cancer cells to be more responsive to other treatments, such as chemotherapy.
Example: HGS-ETR1 and HGS-ETR2
HGS-ETR1 (mapatumumab) and HGS-ETR2 (lexatumumab) are examples of apoptosis-inducing therapies. Both drugs are monoclonal antibodies. One binds to Death Receptor 4 and the other binds to Death Receptor 5.
To the receptors, the drugs look just like the signaling molecule TRAIL. So, the antibodies activate the pro-death signaling pathways that TRAIL usually triggers.
Death Receptors 4 and 5 tend to be more highly expressed in cancer cells than in normal cells. This is important because drugs that target these death receptors may be able to induce apoptosis in cancer cells while only minimally affecting normal cells.
HGS-ETR1 & HGS-ETR2
HGS-ETR1 (mapatumumab) is currently being tested in clinical trials for the treatment of adults with relapsed or refractory multiple myeloma. Clinical trials are also evaluating HGS-ETR2 (lexatumumab) in pediatric patients with relapsed or refractory lymphoma or solid tumors, including Ewing sarcoma.
Normal Blood Vessel Formation
The creation of new blood vessels—a highly regulated process called angiogenesis—primarily takes place during early development, when the circulatory system is being formed. In adults, however, angiogenesis normally occurs only to facilitate wound healing or to support various aspects of female reproduction and pregnancy.
On a cellular level, the process of angiogenesis involves a cry for help from a nearby cell that is in need of nutrients or oxygen. The cell releases proteins that specifically seek out and bind to receptors on the surface of endothelial cells that make up blood vessels.
In response to this signal, endothelial cells secrete a special class of proteins called matrix metalloproteinases, or MMPs.
These MMPs clear a path that allows endothelial cells to migrate in the direction of the cell in need and form new blood vessels.
Cancer Cells and Blood Vessel Formation
Once a tumor reaches a certain size (1 cubic millimeter), it requires a blood supply to continue growing. So, tumor cells must find a way to attract new blood vessels. Many tumors release high levels of proteins, such as vascular endothelial growth factor, or VEGF, that bind to and activate the endothelial cells of nearby existing blood vessels.
Tumors can also produce MMPs to help carve pathways for the new blood vessels to follow.
Targeted Therapies Inhibit Blood Vessels
Because angiogenesis is essential for tumors to grow beyond a certain size, blocking angiogenesis is an ideal strategy for cancer therapy. Agents can be developed to interfere with any one of the steps of new blood vessel growth.
Drugs can be designed to bind to either the proteins released from the tumor, or receptors on the endothelial cell surface, to prevent the two from interacting. Efforts can also be made to interfere with the activity of MMPs and prevent them from clearing the road for blood vessel expansion.
The first monoclonal-antibody inhibitor of angiogenesis, Avastin® (bevacizumab), was approved by the Food and Drug Administration (FDA) in 2004. This approval was based on the survival benefit observed in a randomized Phase III trial of first-line treatment of metastatic colorectal cancer. In that trial, bevacizumab, a humanized monoclonal antibody directed against VEGF, was combined with conventional chemotherapy. Bevacizumab therapy also increased overall survival in the first-line treatment of advanced non-small-cell lung cancer when used in combination with standard chemotherapy. In addition to being approved by the FDA for use in patients with metastatic colorectal cancer, bevacizumab is approved for patients with unresectable or recurrent non-squamous non-small cell lung carcinoma. It is also being tested in clinical trials for the treatment of a number of other tumor types.
Two other antiangiogenic drugs, Nexavar® (sorafenib) and Sutent® (sunitinib), have also been approved by the FDA; these are oral small-molecule receptor tyrosine kinase inhibitors. They target multiple receptor tyrosine kinases, including VEGF receptors and platelet-derived growth factor receptors. Sorafenib and sunitinib have been beneficial in the treatment of metastatic renal-cell cancer.
Example: Avastin® (bevacizumab)
When a patient is given Avastin® (bevacizumab), this monoclonal antibody binds to VEGF and keeps it away from receptors on the surface of endothelial cells. Existing blood vessels no longer receive a signal for increased blood flow, so new blood vessels are not formed. This prevents the tumor from continuing to grow.
Example: Nexavar® (sorafenib)
Nexavar® is a small molecule that inhibits multiple kinases—the proteins involved in growth signaling that were described earlier. These kinases include some cell surface receptors as well as enzymes located within the cell.
In addition to blocking the signaling pathways for growth, disrupting kinase signaling also interferes with the tumor's recruitment of new blood vessels.
Nexavar® (sorafenib) is FDA-approved for treatment of advanced renal cell cancer. It is being tested in clinical trials with Avastin® (bevacizumab) to treat advanced melanoma, ovarian cancer, and other advanced-stage solid tumors. Because the kinases targeted by Nexavar® (sorafenib) are also important to some normal cells, therapies like Nexavar® (sorafenib) may affect some normal cells as well.
- A protein that is part of a growth signaling pathway inside the cell is mutated, causing it to become continually active and resulting in the formation of a tumor. What type of targeted therapy might be effective?
- Monoclonal antibody that prevents growth factors from interacting with the receptor
- Monoclonal antibody that holds the growth factor receptor in the "OFF" position
- Small molecule that selectively binds to the mutated protein
- Monoclonal antibody that selectively binds to the mutated protein
- How do cancer cells evade apoptosis?
- Reduce the activity of proteins that detect DNA damage
- Mutation of proteins that induce apoptosis
- Increase the activity of proteins that prevent apoptosis
- All of the above
- Angiogenesis inhibitors will prevent existing blood vessels from delivering oxygen and nutrients to normal cells.
- Correct answer to Question 1: c
- Monoclonal antibody that prevents growth factors from interacting with the receptor - There is a better answer. Since the mutated protein is inside the cell and downstream of the growth factor receptor, preventing the growth factor receptor from being activated is unlikely to overcome the activity of the mutated protein.
- Monoclonal antibody that holds the growth factor receptor in the "OFF" position - There is a better answer. Since the mutated protein is inside the cell and downstream of the growth factor receptor, keeping the growth factor receptor inactive is unlikely to have an effect on the mutated protein.
- Small molecule that selectively binds to the mutated protein - Correct answer. A small molecule would be able to enter the cell and interfere with the activity of the mutated protein.
- Monoclonal antibody that selectively binds to the mutated protein - There is a better answer. A monoclonal antibody cannot easily enter cells so it would not be able to interfere with the activity of the mutated protein.
- Go to Question 2.
Correct answer to Question 2: d
- Reduce the activity of proteins that detect DNA damage - There is a better answer. This is one way that cancer cells can evade apoptosis, but not the only way.
- Mutation of proteins that induce apoptosis - There is a better answer. This is one way that cancer cells can evade apoptosis, but not the only way.
- Increase the activity of proteins that prevent apoptosis - There is a better answer. This is one way that cancer cells can evade apoptosis, but not the only way.
- All of the above - Correct answer. Cancer cells can use a variety of mechanisms to evade apoptosis, such as reducing the activity of proteins that detect problems within the cell, mutation of proteins that induce apoptosis or reduction of their activity, and increasing the activity of proteins that prevent apoptosis.
- Go to Question 3.
Correct answer to Question 3: b
- True - There is a better answer. Angiogenesis inhibitors do not affect established blood vessels, such as those that deliver oxygen and nutrients to normal adult cells. Angiogenesis only occurs in a few situations in adults.
- False - Correct answer. Angiogenesis inhibitors affect the formation of new blood vessels, but they do not interfere with the already existing blood vessels that deliver oxygen and nutrients to normal adult cells.
The therapies discussed in the previous section target many processes and pathways used by cancer cells to survive and grow. We saw how antibodies, such as Herceptin® (trastuzumab), Avastin® (bevacizumab), and TRAIL-like antibodies, can disrupt cancer as it signals for uncontrolled growth. Monoclonal antibodies can also be used to design immunotherapies to attack cancer cells.
Monoclonal antibodies can directly trigger an immune response against cancer cells.
Example: Rituxan® (rituximab)
Rituxan® (rituximab) is a good example of a monoclonal antibody that can activate the immune system to attack a cancer cell. It binds to a surface protein, called CD20, located on mature B lymphocytes (B cells). Once bound, the antibody activates the body's immune system, which then attacks the cancer cells. Rituxan® (rituximab) may also make cells more susceptible to chemotherapy, promoting more cell death by apoptosis.
Because CD20 is on all B cells, Rituxan® (rituximab) kills normal as well as cancer cells. However, patients can regenerate normal B cells from their own or transplanted blood stem cells.
Clinical trials have shown that Rituxan® (rituximab) can be effective against cancer cells that express CD20 when used with standard chemotherapy regimens such as CHOP—which includes cyclophosphamide, doxorubicin, vincristine, and prednisone—or CVP—which includes cyclophosphamide, vincristine, and prednisone. Combination therapy with Rituxan® (rituximab) and chemotherapy has been approved by the Food and Drug Administration (FDA) for the treatment of certain types of non-Hodgkin lymphoma. Three possible mechanisms of Rituxan-mediated cell lysis have been proposed: (1) antibody-dependent cell-mediated cytotoxicity, (2) complement-dependent cytotoxicity, and (3) apoptosis (independent of immune system). Antibody-dependent cell-mediated cytotoxicity occurs when immune cells (including natural killer cells, T cells, and macrophages) bind to Rituxan and release chemicals that result in cell lysis. Complement-dependent cytotoxicity occurs when Rituxan recruits complement proteins, which disrupt the cell's plasma membrane, leading to cell lysis. Rituxan may also induce target cells to undergo apoptosis independent of the immune system.
Monoclonal antibodies can be chosen for their ability to target specific receptor proteins on the outside of cancer cells and then be modified to also deliver lethal molecules to these cancer sites. Radioactive isotopes can be attached—or conjugated—to carefully chosen monoclonal antibodies. When the conjugated antibody binds to a specific target on the cancer cell's surface, the radiation will fatally damage the cell.
Example: Bexxar® (tositumomab)
Bexxar® (tositumomab) is an example of a radioactive immunotoxin. It is a monoclonal antibody that binds to CD20. Radioactive iodine attached to the antibody releases high doses of radiation that will kill the cell.
Because CD20 is on all B cells, Bexxar® (tositumomab) kills normal cells as well as cancer cells. The radiation released from Bexxar® (tositumomab) may also damage nearby cells that do not have CD20 on their surface. However, patients can create new normal B cells from their own stem cells or transplanted stem cells.
Bexxar® (tositumomab and iodine I 131 tositumomab) has been approved by the FDA for the treatment of patients with follicular non-Hodgkin lymphoma whose disease is refractory to Rituxan® (rituximab) and who have relapsed following chemotherapy. Bexxar® (tositumomab) is also being evaluated for use as a first-line therapy in clinical trials.
Monoclonal antibodies can also be conjugated to other types of molecules that are toxic to cells.
Example: Mylotarg® (gemtuzumab)
When Mylotarg® (gemtuzumab) binds CD33, the cell's plasma membrane folds in and the antibody is brought inside the cell.
Once inside, Mylotarg® (gemtuzumab) releases its secret weapon—a cytotoxic antibiotic. The drug travels into the nucleus, where it binds DNA. Like some standard chemotherapy drugs, this drug causes breaks in the DNA. If the breaks remain unrepaired they eventually lead to cell death.
CD33 is expressed on some normal blood cells, but not on stem cells. This means that, although a patient's normal cells may be killed along with the cancer cells, the stem cells will be able to replace the normal cells over time.
Mylotarg® (gemtuzumab ozogamicin) is currently approved by the FDA for treatment of some AML patients who have relapsed and are unable to undergo treatment with standard chemotherapy. It is also being tested in clinical trials for earlier stage AML and other types of cancer.
Vaccines can also be used to activate a patient's immune system to attack cancer. Unlike monoclonal antibodies and other types of targeted therapies, cancer vaccines do not act directly on cancer cells. Instead, they work systemically to activate the body's immune system.
No vaccine has yet been approved by the FDA to treat cancer. However, researchers are actively testing several approaches for therapeutic cancer vaccines.
Example: Dendritic Cell Vaccines
One therapeutic cancer vaccine approach takes advantage of a specialized type of immune cell called a dendritic cell.
Dendritic cells detect and chew up foreign "invader" proteins and then "present" pieces of the invaders on their surface.
Certain populations of killer T cells—another type of immune cell—recognize these foreign pieces and increase in number, creating an army of immune cells to attack cells bearing the invader protein.
To make a dendritic cell vaccine, the blood of the cancer patient is collected and enriched to increase the population of dendritic cells. These cells are then grown in the laboratory in the presence of a protein or part of a protein that is present in or on the patient's tumor cells.
The patient's dendritic cells digest the protein and transport tiny pieces of it to the cell surface. When the dendritic cells are put back into the patient, they signal certain populations of killer T cells to destroy all cells with the telltale protein, including cancer cells.
- The primary mechanism by which Mylotarg® (gemtuzumab) kills cancer cells is by blocking CD33 signaling.
- Monoclonal antibodies are a type of vaccine.
- Correct answer to Question 1: b
- True - Incorrect answer. Mylotarg® (gemtuzumab) simply uses CD33 to localize a cytotoxic drug to the cancer cell. It is this cytotoxic drug—not the interaction of Mylotarg® (gemtuzumab) with CD33—that actually kills the cell.
- False - Correct answer. The primary mechanism by which Mylotarg® (gemtuzumab) kills cancer cells is the toxic effect of the drug that is conjugated to the antibody.
- Go to Question 2.
Correct answer to Question 2: b
- True - Incorrect answer. Antibodies are a form of immunotherapy, but they are not a vaccine. Antibodies are sometimes referred to as passive immunotherapy because they are not produced by the patient's body. In contrast, vaccines involve the administration of a substance that causes the patient's immune system to mount a targeted attack on a specific antigen.
- False - Correct answer. Although they are a form of immunotherapy, monoclonal antibodies are not considered vaccines. Antibodies are sometimes referred to as passive immunotherapy because they are not produced by the patient's body. In contrast, vaccines involve the administration of a substance that causes the patient's immune system to mount a targeted attack on a specific antigen
Developing New Targeted Therapies
Research to Identify Potential Targets
Scientists are making exciting progress in discovering new targets and designing appropriate therapies for cancer. This section will show you a variety of techniques that are used to identify new potential targets in cancer.
Ways to Identify Targets
As you have seen throughout this tutorial, several targets have been identified already, but researchers are still looking for new and better targets. Researchers use a variety of techniques to identify potential targets for cancer therapy. Some look at whole chromosomes for abnormalities while others study tell-tale changes in gene or protein-expression levels in a cancer cell when it is compared to a normal counterpart. This narrows the search for targets.
Comparative Genomic Hybridization
One approach researchers are using is to look at the chromosomes of cancer cells and compare them to those of normal cells. Many cancer cells gain or lose large sections of chromosomes. Other cancer cells even rearrange sections of their chromosomes through a process called translocation.
A clinical test commonly used to find these changes is called Comparative Genomic Hybridization, or CGH. If researchers identify abnormal gains or losses of chromosomal regions in the genome associated with cancer cells or with cancer types, they can then use molecular biology to determine exactly which of these genes may be involved in cancer.
Gene Expression Profiling
Gene expression or genomic profiling is another way to compare and contrast cancer cells with normal cells. DNA microarrays, sometimes called "gene chips," allow researchers to "see" the expression of hundreds or thousands of genes all at once.
Using normal profiles for comparison, researchers analyze the information collected from thousands of genes in cancer cells to determine which pathways might be contributing to cancer cell growth. For example, cancer cells may express a gene for a certain cell surface protein that is not present in normal cells. This protein may be a good target for monoclonal antibody-based therapy or a cancer vaccine.
Oncotype DX™ (http://www.genomichealth.com/oncotype) is a clinically validated genomic-profiling test that helps predict the likelihood of breast cancer recurrence in women with newly diagnosed, early stage invasive breast cancer. Oncotype DX can also help assess the benefit from chemotherapy.
It is also possible to look at global patterns of protein expression using proteomics. Proteins that exhibit differences in cancer cells versus normal cells can be purified and identified. Efforts are also being made to identify differences in protein expression levels and in their function in cancer cells when compared to normal cells.
For many proteins in the cell, the addition of a small chemical group known as a phosphate acts as a switch that activates them. This process is called phosphorylation. Proteomics techniques preserve a cell's phosphorylation state and capture an accurate picture of which proteins interact in a cancer cell. Biopsy samples are treated with enzymes to block the removal of phosphates from proteins. This enables researchers to identify a protein pattern almost identical to what was in the cell at the time of collection.
Researchers usually discover a possible cancer target by first studying animal models, large panels of different types of cancer tissues collected from cancer patients' biopsies, or cancer cell lines. Next they show that they understand how the pathway or process they have chosen actually works in cancer cells. This is called "validating" the target.
Emerging Targeted Therapies
Researchers are pursuing a number of molecules and pathways they think may be good therapeutic targets. These include a "molecular chaperone" protein called HSP90, a cellular regulatory protein called mTOR, a DNA repair protein called PARP, and a pro-growth receptor called IGF1R, as well as many others.
Preparing for Clinical Trials
If all of the experiments in cancer cells and animal models indicate that a target may be important for cancer cell growth, researchers will begin to think about interfering with the target in cancer patients.
Finding Good Treatments for Targets
Once a target is identified, clinical studies of a new treatment that can interfere with this target need to be designed. The type of drug developed and tested depends on the target. If the target is a cell surface receptor, a monoclonal antibody might be a good option.
If the target is inside the cell, a small molecule would probably be better.
Once a drug is found, it must pass the "proof of principle" test in the laboratory. Experiments are done in cell lines and animals to show that the treatment can interfere with cancer's progress without causing too much collateral damage to normal cells and tissues. Animal models are also used to see how the drug is metabolized.
The drug must be designed so that it is suitable for use in patients. It must also be possible to mass-produce the agent so sufficient quantities can be made available for clinical trials and general clinical use if treatment is shown to be effective.
Clinical studies of targeted therapies must also involve an appropriate patient population. The question must be asked: Does this patient have the target that should respond to this new treatment? In some cases, all or most patients with a certain type of cancer will have the appropriate target.
In other cases, genomic profiling or another technology is used to identify patients with different types of cancer who all share the same appropriate target. When the latter occurs, patients with different types of cancer may be enrolled in the same trial to study a new targeted therapy.
Before treatments like targeted therapies can become commercially available for the treatment of cancer patients, they must be approved by the Food and Drug Administration (FDA). In order to obtain FDA approval, clinicians must show that the new treatment is safe and effective in clinical trials. Clinical trials are done in several different phases, each of which has a different goal.
Exploratory Investigational New Drugs (IND) Trials
The FDA now allows researchers to do some preliminary tests of their drug candidates in humans. The goal is to get information early about whether the new treatment truly does hit its intended target. These studies are sometimes called Phase 0 clinical trials, or may be referred to as early Phase I or exploratory Investigational New Drug trials.
Patients who volunteer to participate in a Phase 0 clinical trial are given small doses of a drug. Researchers then perform tests to see whether the drug can get to its target and whether the target is affected by the drug. This information lets researchers know whether they are on the right track or whether they need to go back and make modifications to their drug.
Phase 0 trials do not provide information about whether a drug will be effective against a given disease, in part because the dose of drug given is very low, the duration of therapy is short, and the number of patients treated is small.
Phase I - Testing Safety
If the results of Phase 0 and/or preclinical studies are promising, a Phase I trial is done. Phase I trials are generally very small, involving only 15 to 30 people.
There are three primary goals of Phase I trials:
- The first is to find a good dose for the drug. Usually, patients are given a low dose of the drug, which is slowly increased until unacceptable side effects are observed.
- The second goal of a Phase I trial is to learn more about how a drug is metabolized and cleared by the body. This helps researchers decide how the drug should be administered and how often.
- The third goal is to identify negative side effects caused by the drug.
Finding out how well a drug works against a particular disease is not a primary goal of Phase I clinical trials. Participants in Phase I trials for cancer drugs are usually patients whose cancer has not responded to standard treatments.
Phase II - Testing Efficacy
If no serious risks are identified during the Phase I trial, a Phase II trial is done. Phase II trials are larger than Phase I trials—usually around 100 people—and involve patients who have not responded to standard treatments or have a form of cancer for which there is no standard treatment. Participants in Phase II clinical trials continue to be closely monitored for side effects; however, information is also collected about whether the drug is effective.
Targeted Therapies & Early-Phase Trials
Clinical trials can evaluate a drug's effectiveness using one or more of several criteria, or endpoints. Most of these are the same for targeted therapies and other types of drugs. The ultimate measure of a drug's efficacy is whether it extends the survival or increases the quality of life for patients. However, since it can sometimes take many years to determine if a drug increases survival, clinical trials sometimes have endpoints that can be evaluated in the short term.
One unique aspect of targeted therapies is that measurements are often done to determine whether the therapy is affecting its target. For example, if a targeted therapy is designed to inhibit a kinase, an assay might be done to see if a protein that is normally phosphorylated by the kinase is less phosphorylated in a patient's cancer cells. If the targeted therapy is a vaccine, an assay might be done to see if the patients who received the vaccine have mounted an immune response against the target. Target-specific outcomes are often looked at in Phase I and Phase II clinical trials.
Phase III - Efficacy in Larger Populations
If the Phase II trial results suggest that a drug may be effective, additional patients are recruited for a Phase III trial. Phase III trials involve large numbers of people—from 100 up to thousands. The goal of Phase III trials is to determine whether the new therapy is either more effective or less harmful than a current standard treatment.
The FDA's decision to approve a drug for general use often hinges on the results of Phase III clinical trials. This decision is primarily based on whether the clinical trials show that the benefits of the new drug outweigh its risks.
Targeted Therapies & Late-Phase Trials
A few targeted therapies—such as Herceptin® (trastuzumab)—have already been shown to increase overall survival. But effectiveness of most targeted therapies is still being studied in clinical trials. Because targeted therapies are designed to selectively attack tumor cells, it is hoped that they will not be as toxic as standard chemotherapy. Although standard chemotherapy has saved many lives, it often has severe side effects, some of which are long-lasting.
Many clinical trials are also exploring how targeted therapies can be used in combination with standard treatments or with one another. The addition of a targeted therapy may allow standard chemotherapy drugs or radiation therapy to be used at lower doses, which may help limit toxicity. In some cases, targeted therapies may even make tumors more responsive to standard chemotherapy drugs or radiation treatments. And some combinations of targeted therapies are effective because they are able to block tumor growth and angiogenesis signaling at the same time.
Phase IV - Long-Term Effects
After they receive FDA approval, some drugs continue to be monitored for long-term safety and efficacy through Phase IV clinical trials. These trials, which are sometimes called post-launch or post-marketing trials, evaluate the safety and efficacy of drugs in a standard clinical, or "real world," setting.
Phase IV trials may or may not compare new treatments with others. They are usually open-label studies, meaning that patients know exactly which treatments they are receiving, and they typically involve large numbers of patients recruited from a combination of community physician and academic medical centers.
Risks of Targeted Therapy
This tutorial has explained the evidence-based design of targeted therapies and has shown the benefits of taking a more precise aim at specific cancer pathways and processes. However, like all new cancer treatments, targeted therapies are not without risks.
Drug resistance can develop in patients given targeted therapies as it does when standard chemotherapy is given. Sometimes resistance to therapy occurs because the target itself mutates, so the new therapy is unable to interact with its target as it did earlier.
Other times, the resistance is indirect, in that the tumor finds a new pathway to achieve tumor growth in spite of the presence of a targeted therapy that is successfully blocking its assigned target.
Clinicians do not know whether using targeted therapies to treat cancer will trigger new side effects. They do not know how long treatment can continue and in what combinations targeted therapies will be most effective. They also do not know if cancer cells can establish alternate pathways to continue their growth when a targeted therapy successfully disrupts an existing one. The clinical trials currently under way are trying to answer these questions and others as they arise.
FDA-Approved Targeted Therapies
Several targeted therapies have already been approved by the FDA for the treatment of cancer, and the number will likely increase as research continues to take place. The targeted therapies listed below are approved by the FDA for specific cancer indications. These drugs continue to be studied in clinical trials for various types of cancer. For each generic drug name listed, the brand name is shown in parentheses. Additional information about these drugs can be found at http://www.cancer.gov/cancertopics/druginfo/alphalist.
- Mechanism: Humanized monoclonal antibody against CD52 antigen (expressed on lymphocytes)
- Indications: B-cell chronic lymphocytic leukemia in patients for whom alkylating agents have failed
- Toxicities: Myelosuppression
- Mechanism: Humanized monoclonal antibody against vascular endothelial growth factor (VEGF)
- Indications: First-line treatment for metastatic colorectal cancer
- Toxicities: Hypertension, intestinal perforation (rare)
- Mechanism: Proteasome inhibitor
- Indications: Multiple myeloma relapsed after two prior treatments
- Toxicities: Gastrointestinal symptoms, fatigue, thrombocytopenia, and sensory neuropathy
- Mechanism: Chimeric monoclonal antibody against epidermal growth factor receptor (EGFR)
- Indications: E GFR-positive, irinotecan-refractory metastatic colorectal carcinoma
- Toxicities: Acne-like rash, folliculitis (inflammation of hair follicles), hypersensitivity reactions
- Mechanism: Tyrosine kinase inhibitor
- Indications: Third-line treatment of non-small cell lung cancer
- Toxicities: Diarrhea, nausea, rash, pulmonary toxicity
- Mechanism: Cytotoxic antibiotic calicheamicin linked to a humanized monoclonal antibody against CD33 antigen (expressed on myeloid cells)
- Indications: CD33-positive acute myeloid leukemia in patients older than 60 years who are not candidates for cytotoxic therapy
- Toxicities: Myelosuppression
- Mechanism: Radioisotope yttrium linked to a mouse monoclonal antibody against CD20 antigen (expressed on mature B cells)
- Indications: Low-grade and follicular B-cell non-Hodgkin lymphoma refractory to rituximab
- Toxicities: Neutropenia, thrombocytopenia
- Mechanism: Inhibitor of Bcr-Abl and c-kit tyrosine kinases
- Indications: Chronic myelogenous leukemia and gastrointestinal stromal tumors
- Toxicities: Nausea, diarrhea, myalgia, edema
- Mechanism: Chimeric monoclonal antibody against CD20 antigen (expressed on mature B cells)
- Indications: Refractory low-grade and follicular B-cell non-Hodgkin lymphoma
- Toxicities: Infusion-related symptoms: fever, chills, nausea, urticaria (hives)
- Mechanism: Radioisotope iodine 131 linked to a chimeric monoclonal antibody against CD20 antigen
- Indications: Follicular non-Hodgkin lymphoma, with or without transformation (increased aggressiveness), that has relapsed after chemotherapy and is refractory to rituximab
- Toxicities: Myelosuppression
- Which of the following types of clinical trials measure how well a targeted therapy works against cancer?
- Phase I
- Phase II
- Phase III
- Phase II and Phase III
- Phase I, Phase II, and Phase III
- Correct answer to Question 1: d
- Phase I - There is a better answer. The primary goals of Phase I clinical studies are to identify toxicities and establish a dose and treatment approach for treating patients. Although there is a possibility that a beneficial effect may be observed in Phase I trials, this is not one of the primary endpoints.
- Phase II - There is a better answer. Phase II clinical trials do measure the efficacy of a drug, but efficacy is also measured during another phase.
- Phase III - There is a better answer. Phase III clinical trials do measure the efficacy of a drug, but efficacy is also measured during another phase.
- Phase II and Phase III - Correct answer. Both Phase II and III trials assess drug efficacy.
- Phase I, Phase II, and Phase III - There is a better answer. Although Phase II and III trials do assess drug efficacy, the primary goals of Phase I trials do not include measurement of efficacy. Phase I trials attempt to identify toxicities and establish a dose and treatment approach for treating patients.
Summary and Conclusions
Summary and Conclusions
Clinical trials are finding ways to use targeted therapies to effectively treat cancer. Since dozens of new, innovative targeted therapies have not yet been approved by the Food and Drug Administration (FDA), clinical trials may be the only opportunity for patients to access them at present. Unfortunately, only 3 percent of adults with cancer choose this route and enroll in clinical trials.
A recent study has indicated that 65 percent of patients would have been receptive to clinical trial enrollment if they had been made aware of the option at the time of initial diagnosis.
Eighty-seven percent of patients would consider participating in a clinical trial if their initial treatment failed.
Physicians have the responsibility to talk to their patients about clinical trials and help them identify appropriate trials if the patients are interested.
Finding Clinical Trials
There are targeted therapies for cancer in all phases of clinical study. Many of these targeted therapies target the cellular processes discussed in this tutorial.
To do your own search for clinical trials, visit the National Cancer Institute's (NCI) Web site at http://www.cancer.gov/clinicaltrials, where you can find clinical trials run by many different cancer centers around the country.
Alternatively, you can search for trials being conducted at the NIH Clinical Center in Bethesda, Maryland at http://bethesdatrials.cancer.gov.
Searches for clinical trials can also be performed at the NIH Web site http://www.clinicaltrials.gov, which contains information about clinical trials sponsored by the NCI, pharmaceutical companies, medical centers, and other groups from around the world.
Additional information about cancer clinical trials can be found on the NCI Web site at http://www.cancer.gov/clinicaltrials.
For answers to additional questions about cancer, contact NCI’s Cancer Information Service (CIS). The CIS offers comprehensive research-based information for patients and their families, health professionals, cancer researchers, advocates, and the public, as well as help with clinical trial searches. The CIS’s points of contact are as follows: