 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 targets within cancer cells and then to design therapies 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. Healthcare 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 FDA approved? How can I find clinical trials that are evaluating targeted therapies? 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 in areas such as 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 are present in all rapidly dividing cells, many normal cells throughout the body that are undergoing active growth and cell division can also be damaged. 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 it 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. Target therapies 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. The best target for therapy is a molecular pathway that is present in cancer cells and absent in normal cells. This ensures that the therapy will only attack cancer cells. Fortunately, 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. 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. 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. Glevec is one example of a small molecule targeted therapy that inhibits a few key signaling pathways. 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. Second, they can also be used as delivery vehicles, guiding radioactive molecules or toxins to the cancer cells. Third, antibodies attached to a cell can trigger an immune response that destroys the cell. Herceptin, Avastin, Bexar, Mylotarg, and Rituxin are examples of monoclonal antibodies used to treat cancer. 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. 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 the receptors on the surface of the cell. In many cases, 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 molecules called phosphates from one member of the relay team to the next. Receptors in 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 cells 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 a 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 or cancer cells growth factor receptors can block the receptors from interacting with their growth factor to 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. One example of a therapy designed to target a cell surface receptor is Herceptin. Herceptin 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 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 may also interfere with cancer cell growth by activating an immune response. Glevec is a small molecule that blocks the signaling activity of certain proteins inside a cell. Proteins bound by Glevec cannot function in their relay team. They can no longer transmit phosphorylation signals along the pathways that lead to cell growth and division. Glevec can inhibit several different proteins, including two proteins involved in growth signaling. We have shown that growth pathways and growth inhibition pathways regulate cell growth. Now we will look at another way normal cells can 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 program 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. 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, can cause apoptosis when it binds to either death receptor 4 or death receptor 5. The decision to undergo apoptosis depends on the balance of pro-apoptotic and pro-survival signaling pathways. 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. 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 BCL2. 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. HGS ETR1 and HGS ETR2 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 trail. So the antibodies activate the pro-death signaling pathways the 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 disturbing normal cells. 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, angiogenesis normally occurs only to facilitate wound healing or 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 metalloproteases or MMPs. These MMPs clear a path that allows endothelial cells to migrate and grow in the direction of the cell in need. Once a tumor reaches a certain size, one cubic millimeter, it requires a blood supply to continue growing. So tumors 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 a path for the new blood vessel to follow. 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. When a patient is given a vastan, 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. Nexivar 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. 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, a vastan, 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. Rituxin 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 cells. Once bound, the antibody activates the body's immune system, which then attacks the cancer cells. Rituxin may also make cells more susceptible to chemotherapy, promoting more cell death by apoptosis. Because CD20 is on all B cells, Rituxin kills normal as well as cancer cells. However, patients can regenerate normal B cells from their own or transplanted blood stem cells. 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. Bexar is an example of a radioimmunotoxin. It is a monoclonal antibody that binds to a protein called CD20 that is found on the surface of both normal and cancerous B cells. Radioactive iodine attached to the antibody releases high doses of radiation that can kill the cell. Because CD20 is on all B cells, Bexar kills normal as well as cancer cells. The radiation released from Bexar may also damage nearby cells that do not have CD20 on their surfaces. However, patients can regenerate normal B cells from their own stem cells or transplanted stem cells. Monoclonal antibodies can also be conjugated to other types of molecules that are toxic to cells. Mylotargh is a monoclonal antibody that binds to a protein called CD33. CD33 is on the surface of cancer cells of almost all patients with acute myeloid leukemia or AML. When mylotargh binds CD33, the cell membrane folds in and the antibody is brought inside the cell. Once inside, mylotargh 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. Vaccines can also be used to generally 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. There are not yet any FDA-approved cancer vaccines that are used for treatment. However, researchers are actively testing several approaches for therapeutic cancer 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 a telltale protein, including cancer cells. 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. 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 telltale 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. 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 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 a conjugated monoclonal antibody or a cancer vaccine. 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 molecule called phosphate acts as a switch that activates the protein. This process is called phosphorylation. Proteomics techniques preserve a cell's phosphorylation state and capture an accurate pattern 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. 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 regulator of cellular bioenergetics called MTOR, a DNA repair protein called PARP, and a pro-goth receptor called IGF1R, as well as many others. 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 a target in cancer patients. 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 of treatment as 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 other 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 onto the same trial to study a new targeted therapy. Before treatments like targeted therapies can become commercially available for treatment of cancer patients, they must be approved by the 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. The FDA now allows researchers to do some preliminary tests of their drug candidates and 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 zero clinical trials, or may be referred to as early phase one or exploratory investigational new drug trials. Patients who volunteer to participate in a phase zero 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 zero trials do not provide information about whether a drug will be effective against a given disease, in part because the dose of a drug given is very low, the duration of therapy is short, and the number of patients treated is small. If the results of phase zero and or pre-clinical studies are promising, a phase one trial is done. Phase one trials are generally very small involving only 15 to 30 people. There are three primary goals of phase one trials. The first is to find a good dose for the drug. Usually, patients are given a low dose of the drug, which is solely increased until unacceptable side effects are observed. The second goal of a phase one 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 one clinical trials. Participants in phase one trials for cancer drugs are usually patients whose cancer has not responded to standard treatments. If no serious risks are identified during the phase one trial, a phase two trial is done. Phase two trials are larger than phase one 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 two clinical trials continue to be closely monitored for side effects. However, information is also collected about whether the drug is effective. If the phase two trial results suggest that the drug may be effective, additional patients are recruited for a phase three trial. Phase three trials involve large numbers of people, from 100 up to thousands. The goal of phase three trials is to determine whether the new therapy is either more effective or less harmful than a current standard treatment. The FDA decision to approve a drug for general use often hinges on the results of phase three clinical trials. This decision is primarily based on whether the clinical trials show that the benefits of the new drug outweigh its risks. After they receive FDA approval, some drugs continue to be monitored for long-term safety and efficacy through phase four 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 four trials may or may not compare new treatments with others. They are usually open-labeled 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. 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 the 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 destroys an existing one. The clinical trials currently underway are trying to answer these questions and others as they arise. Several targeted therapies have already been approved by the FDA for treatment of cancer, and the number will likely increase as research continues to take place. Visit the FDA and NCI websites for additional information about clinical trials. Clinical trials are finding ways to use targeted therapies to effectively treat cancer. Since dozens of these new innovative targeted therapies have not yet been approved by the FDA, clinical trials may be the only opportunity for patients to access them at present. Unfortunately, only 3% of adults with cancer choose this route and enroll in clinical trials. A recent study indicated that 65% of patients would have been receptive to clinical trial enrollment if they had been made aware of the option at the time of the initial diagnosis. 87% 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. To do your own search for clinical trials, visit the National Cancer Institute's Physician Data Query, or PDQ, database. Searches for clinical trials can also be done at clinicaltrials.gov. This database contains information about clinical trials that are sponsored by the National Cancer Institute, pharmaceutical companies, medical centers, and other groups from around the world. 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. Additional information about cancer clinical trials can be found on the NCI website at cancer.gov, as well as cancer.gov backslash clinical trials, where a cancer patient can find clinical trials run by many different cancer centers around the country, or at BethesdaTrials.cancer.gov, which will help a patient find cancer trials at the NIH Clinical Center in Bethesda, Maryland. For answers to additional questions about cancer, visit the National Cancer Institute Cancer Information Service website at cis.nci.nih.gov. The website includes a link for accessing live help, a live online service that provides information about cancer, including information about ongoing clinical trials. The public also may contact the Cancer Information Service at 1-800-4-CANCER.