Genetic testing for targeted therapy
- What is targeted therapy?
- Differences between Targeted Therapy and Chemotherapy
- How are targets for targeted therapies determined?
- Types of targeted therapies
- How to determine if a patient is a targeted therapy candidate?
- The limitations of targeted cancer therapy
- List of localizations and drugs approved by the FDA
Targeted therapy
is a type of anti-tumor treatment that uses drugs and a number of other substances that interact with certain molecules («molecular targets») of tumor cells and block their growth, reproduction and spread.
Target drugs are sometimes called «molecularly targeted drugs,» «precision drugs,» or similar names.
Many targeted cancer therapies have been approved by the Food and Drug Administration (FDA) to treat certain types of cancer.
Others are being studied in clinical trials (human studies), and many others are in preclinical trials (animal studies).
Differences between Targeted Therapy and Chemotherapy
Targeted therapy
- Affects specific molecular structures (targets) of tumor cells
- Developed and selected specifically for interacting with a particular target, i.e. selective and specific
- Often cytostatic (that is, it blocks the division of tumor cells)
- Uses information about human genes and proteins to prevent, diagnose, and treat diseases
- Is currently the main area of development of antitumor drugs
Chemotherapy
- Affects all rapidly dividing normal and tumor cells
- Non-specific and non-selective
- Cytotoxic (i.e., it destroys the cells it targets)
How are targets for targeted therapies determined?
Comparison of the number of proteins
One approach to identifying potential targets is to compare the amounts of certain proteins in tumor cells with those in normal cells (differential expression).
Proteins that are present in tumor cells but absent in normal cells, or whose levels are higher in tumor cells, can be potential targets, especially if they are known to be involved in cell growth or survival.
Human epidermal growth factor receptor 2 (HER-2) protein is actively produced on the surface of some tumor cells. Several targeted therapies target HER-2. For example, trastuzumab (Herceptin) is approved to treat certain breast and gastric cancers that overexpress HER-2.
Detecting mutations
Another approach to identifying potential targets is to determine whether tumor cells have changes in their DNA sequence (mutations) during which they produce altered proteins that cause tumor progression and metastasis.
The BRAF cell growth-signaling protein is present in an altered form (known as BRAF V600E) in many melanomas. Vemurafenib (Zelboraf) targets this mutant form of the BRAF protein and is approved to treat patients with inoperable or metastatic melanoma containing this altered BRAF protein.
Searching for abnormalities in chromosomes
Researchers also look for abnormalities in chromosomes that are present in tumor cells but not in normal cells. Sometimes these chromosomal abnormalities lead to the creation of a hybrid (chimeric, fusion) gene, a gene that includes parts of two different genes, the product of which can lead to tumor development. Such hybrid proteins are potential targets for targeted therapies.
Imatinib mesylate (Glivec) targets the chimeric BCR-ABL protein, which consists of parts of two genes that join together in leukemia.
Many different targeted therapies have been approved to treat cancer
Hormone therapy
Slows or stops the growth of hormone-sensitive tumors. Hormone therapy prevents or interferes with the body’s production of hormones that cause tumor growth. Hormone therapy has been approved for breast cancer and prostate cancer.
Apoptosis inducers
Induce a process of controlled death of tumor cells called apoptosis.
Apoptosis is one of the processes the body uses to get rid of unwanted or abnormal cells, but tumor cells have ways to avoid apoptosis. Apoptosis inducers can bypass these ways, causing malignant cells to die.
Angiogenesis inhibitors
Angiogenesis inhibitors block the growth of new blood vessels that feed the tumor (a process called tumor angiogenesis).
Blood provides the oxygen and nutrients that tumors need to continue to grow. Therapies that block angiogenesis can slow and prevent tumor growth. Some targeted therapies inhibit the activity of vascular endothelial growth factor (VEGF), a stimulator of new blood vessel formation. There are angiogenesis inhibitors that target other molecules that stimulate new blood vessel growth.
Immunotherapy
Immunotherapy helps the human immune system destroy tumor cells. Some immunotherapies are monoclonal antibodies that recognize certain molecules on the surface of tumor cells. Binding of the monoclonal antibody to the target molecule results in the destruction of the cells producing that target molecule.
Other monoclonal antibodies bind to certain immune cells to help them better recognize and eliminate tumor cells.
Monoclonal antibodies
Monoclonal antibodies that deliver toxic molecules can cause tumor cell death. Once the antibody binds to its target cell, the toxic molecule bound to the antibody, such as a radioactive substance or cytotoxic chemical compound, is absorbed by the cell, eventually destroying it. The toxin will not affect cells that lack a target for the antibody, that is, the vast majority of cells in the body.
Signal transduction inhibitors
Signal transduction inhibitors block the activity of molecules involved in signal transduction, the process by which a cell responds to external signals. In the process of transforming a normal cell into a malignant one, the latter is continuously stimulated to continuously divide and immortalize without a signal from external regulators (growth factor proteins).
Modulators of gene expression
Modulators of gene expression are substances that alter the function of gene expression regulator proteins in tumor cells, thereby affecting their growth, development and division.
How to determine if a patient is a targeted therapy candidate?
Most patients with certain types of cancer already have a suitable molecular target, potentially defining them as candidates for targeted therapies. For example, in chronic myeloblastic leukemia, most patients have a chimeric BCR-ABL gene, a target for the targeted drug Imatinib.
In other types of cancer, the patient’s tumor tissue must be carefully examined to determine if a suitable target is present. The use of targeted therapy is limited to patients whose tumor has a specific gene mutation encoding a target.
In some cases, a patient is a candidate for targeted therapy only if he or she meets certain criteria (e.g., recurrent disease, locally advanced, metastatic or inoperable cancer). These criteria are set by the regulatory agency when approving the indication for a particular targeted therapy.
What are the limitations of targeted cancer therapy?
Targeted therapy has some limitations:
Possible resistance development
Some time after starting therapy, the tumor may become resistant. Resistance can arise through two primary mechanisms:
- A change in the target itself (due to the emergence of a new mutation and/or artificial selection of a pool of tumor cells with a resistant mutation). In this case, the targeted drug is no longer effective.
- Tumor cells find an alternative growth pathway that is independent of the target of the targeted therapy used.
For example, the combined use of two targeted drugs (BRAF and MEK inhibitors), in melanoma with the BRAF V600E mutation, significantly slows disease progression and the development of resistance, compared with the use of a single drug.
Another approach is to use targeted therapy in combination with one or more conventional chemotherapy drugs.
For example, targeted therapy with trastuzumab (Herceptin) in combination with docetaxel, a traditional chemotherapy drug, to treat women with metastatic breast cancer with HER2/neu protein hyperexpression.
Challenging drug development
Another limitation of the current application of targeted therapies is that for some of the identified targets (due to the complexity of their structure and/or regulation in the cell) it is difficult to develop a drug.
An example of such a "target" is the RAS family proteins, components of the signaling pathway of the same name.
To date, there is no inhibitor capable of blocking these proteins, although genetic abnormalities in RAS family genes have been identified in ~25% of all malignant tumors.
What targeted drugs have been approved to treat certain types of cancer?
List of localizations and drugs approved by the FDA
(some types of targeted therapies have been approved to treat more than one type of cancer):
- Soft tissue sarcoma
- Gastrointestinal neuroendocrine tumors
- Giant cell tumor
- Lymphoma
- Malignant mesothelioma
- Multiple myeloma
- Myelodysplastic/ myeloproliferative disorders
- Neuroblastoma
- Hemangioblastoma
- Epithelial tumors of the ovaries/uterine tubes/primary peritoneal cancer
- Plexiform neurofibroma
- Systemic mastocytosis
- Glioblastoma
- Gastrointestinal stromal tumor
