martes, 15 de julio de 2014

Advances in Targeted Therapies Tutorial - National Cancer Institute

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Advances in Targeted Therapies Tutorial - National Cancer Institute



National Cancer Institute at the National Institutes of Health

Advances in Targeted Therapies Tutorial

  • Developing New Targeted Therapies


Developing New Targeted Therapies



In This Section:


Research to Identify Potential Targets

Introduction

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.

This image illustrates a chromosomal translocation involving chromosomes 4 and 13. The genetic material for each chromosome is shown in a different color. Chromosome 4's genetic material is colored cyan, and chromosome 13's genetic material is colored red. For chromosome 4, one normal copy is shown paired with another chromosome that contains part of chromosome 4 fused to part of chromosome 13.
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 genomeassociated 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.

This is a picture of a researcher holding a gene chip with a gloved hand. The picture is titled, 'Gene Chips Show Gene Expression'.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.

This image shows a comparison of a cancer cell (green) and a normal cell (pink). In the cancer cell, there is an arrow pointing to a cell receptor labeled 'Cell Surface Protein'. There is another arrow pointing to the DNA in the nucleus labeled 'Gene for Target Protein'.

More Information

Oncotype DX™

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 fromchemotherapy.

Proteomics

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.

This is a picture of a researcher loading samples into a liquid chromatography-mass spectrometry system, which will isolate and analyze proteins in the sample. The picture is titled 'Proteomics'.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.

Validating Targets

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.

This is a picture of a researcher looking through a microscope at a flask containing cultured cancer cells.

Emerging Targeted Therapies

Researchers are pursuing a number of molecules and pathways they think may be good therapeutictargets. 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.

This is an image of a male torso with a cancerous tumor (green) in the colon. A close-up view shows two receptors sticking out of the membrane of a colon cancer cell. A purple, Y-shaped antibody molecule is attached to one of the receptors and is preventing the receptors from coming together and becoming activated. On the far right is an icon that contains a picture of a purple, Y-shaped antibody molecule and is labeled 'Monoclonal Antibody'.If the target is inside the cell, a small molecule would probably be better.

This is an image of a male torso with a cancerous tumor (green) in the colon. A close-up view shows a string of signaling molecules inside a colon cancer cell. The first three signaling molecules glow yellow, indicating that they are active. The fourth signaling molecule is interacting with a purple targeted therapy molecule. This signaling molecule and all subsequent signaling molecules in the string are gray, indicating that they are inactive.
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.

On the left side of this image is a picture of a cell culture flask on a microscope. On the right is a scientist holding a white mouse. The picture is titled 'Proof of Principle Test'.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.

Identifying Patients

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 this image, a group of 10 people is shown on the left side labeled, 'Patients with Colon Cancer'. Eight people in the group of 10 have purple bull's eyes on them, indicating that they have the target for a cancer therapy. On the right side of the screen is a group of 10 women labeled, 'Patients with Breast Cancer'. None of these patients has the purple bull's eye, indicating that they lack the target for the cancer therapy.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.

In this image, a group of 10 people on the left side is labeled, 'Patients with Colon Cancer'. Eight of 10 people in the group have purple bull's eyes on them, indicating that they have a specific target for cancer therapy. On the right side of the screen is a group of 10 women labeled, 'Patients with Breast Cancer'. In this group, 8 of 10 patients have purple bull's eyes symbols on them, indicating that they also have the specific target for cancer therapy.

Clinical Trials

Introduction

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.

This image is titled, 'Phase 0'. A group of eight cancer patients labeled 'Volunteer Cancer Patients' is shown. A caption at the top of the screen asks questions addressed by Phase 0 trials: 'Does the drug reach the target? Is the target affected?' An icon is shown at the bottom right corner of the screen. It has three symbols representing different types of targeted therapies: a purple, Y-shaped antibody molecule; a syringe filled with a purple liquid; and three purple, oval-shaped small molecules.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.

This image shows a group of 20 cancer patients labeled 'Volunteer Cancer Patients'. The picture is titled 'Phase I'.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.

This image shows a group of about 100 cancer patients labeled 'Volunteer Cancer Patients'. The title at the bottom of the screen says 'Phase II'.

More Information

Targeted Therapies & Early-Phase Trials

Clinical trials can evaluate a drug's effectiveness using one or more of several criteria, orendpoints. 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 responseagainst 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 aPhase 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.

This image shows a large group of people, who represent clinical trial participants, over a map of the United States. The title at the bottom of the screen says 'Phase III'.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.

More Information

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.

This image shows the outline of a map of the United States. Inside the map are a large number of people who have cancer. They represent patients recruited from across the country for post (FDA)-approval clinical trials. The title at the bottom of the screen says 'Phase IV'.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.

This image shows a cut-away view of the inside of a cancer cell. There are multiple receptors spanning the cell membrane. One of the receptors has a red starburst. A close-up view of this receptor is shown and is labeled 'Mutation'. A caption reads, 'Target Mutates'. The image is titled 'Drug Resistance in Targeted Therapies'.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.

This image shows a mass of green cancer cells in the middle of a layer of pink normal cells. The cancer cells are labeled 'Tumor Develops New Growth Pathways'. The picture is titled 'Drug Resistance in Targeted Therapies'.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.

Visit the FDA and NCI Web sites for additional information about clinical trials.

This image shows pages from the FDA and the National Cancer Institute Web sites. The caption contains the two Web site addresses: www.fds.gov and www.cancer.gov.

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 athttp://www.cancer.gov/cancertopics/druginfo/alphalist.

Alemtuzumab (Campath-1H®)

Bevacizumab (Avastin®)

Bortezomib (Velcade®)

Cetuximab (Erbitux®)

Gefitinib (Iressa®)

Gemtuzumab (Mylotarg®)

  • 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
Ibritumomab tiuxetan (Zevalin®)

Imatinib (Gleevec®)

  • Mechanism: Inhibitor of Bcr-Abl and c-kit tyrosine kinases
  • Indications: Chronic myelogenous leukemia and gastrointestinal stromal tumors
  • Toxicities: Nausea, diarrhea, myalgia, edema
Rituximab (Rituxan®)

  • 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)
Tositumomab (Bexxar®)

  • 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
Trastuzumab (Herceptin®)

  • Mechanism: Humanized monoclonal antibody against HER2
  • Indications: Metastatic breast cancer expressing HER2
  • Toxicities: Cardiotoxicity

Self Test

Questions

  1. Which of the following types of clinical trials measure how well a targeted therapy works against cancer?
    1. Phase I
    2. Phase II
    3. Phase III
    4. Phase II and Phase III
    5. Phase I, Phase II, and Phase III
    Check answer.

Answers

  1. Correct answer to Question 1d
    1. 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.
    2. 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.
    3. 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.
    4. Phase II and Phase III - Correct answer. Both Phase II and III trials assess drug efficacy.
    5. 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.

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