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Genetic testing for targeted therapy selection
WHAT IS TARGETED THERAPY?
Targeted therapy
a kind of treatment against cancer using medicine and some other substances that interact with certain molecules («molecular targets») of cancer cells and block their growth, reproduction and spread.
Targeted therapy are sometimes referred to as «molecular targeted agents», «precision medicine» or similar.
Many anticancer targeted agents have been approved by the Food and Drug Administration (FDA) in order to treat certain types of cancer.
Others are being explored in clinical trials (human trials), and many others are in preclinical trials (animal trials).
Targeted therapy and chemotherapy distinction
Targeted Therapy features
- Attacks certain molecular structures (targets) of cancer cells
- Designed and chosen particularly for interaction with a certain target, that is, selective and specific
- Often cytostatic (that is, it precludes cancer cells division)
- Applies human gene and protein data to prevent, make a diagnosis and treat diseases
- Is nowadays the main direction of against cancer drugs elaboration
Chemotherapy features
- Influences on all fastly dividied both normal and cancer cells
- Non-specific and non-selective
- Cytotoxic (meaning it kills the cells it affects)
Target discovery for targeted therapy
Protein amount comparability
One way to recognize potential targets is to compare the amount of certain proteins in cancer cells with those in normal cells (differential expression).
Proteins present in tumor cells but absent in normal ones, or that are higher in tumor cells, can be potential targets, especially if they are known to be involved in cell growth or survival.
An example of comparing the number of individual proteins
The surface of some cancer cells generates a lot of the human epidermal growth factor receptor 2 (HER-2) protein. There are several targeted agents that affect HER-2. For instance, trastuzumab (Herceptin) is approved for certain types of breast and stomach cancers that overexpress HER-2.
Mutation identification
Another way to recognize potential targets is to define if cancer cells have changes in the DNA sequence (mutations) resulting in the altered protein production that cause tumor progression and metastasis.
Changes in the DNA sequence sample
The cell growth signaling protein, BRAF, is frequently present in an altered form (known as BRAF V600E) in melanoma. Vemurafenib (Zelboraf) affects this mutant form of the BRAF protein and is approved for the treatment of patients with unresectable or metastatic melanoma with BRAF mutation.
Chromosomal abnormalities retrieval
Scientists search for chromosomal abnormalities present in cancer cells as opposed to normal ones. These chromosomal abnormalities sometimes brings to the creation of a hybrid (chimeric, fusion) gene that includes parts of two different genes. The protein expressed from newly formated gene can lead to the growth of a cancer. Hybrid proteins are particular aim for targeted therapy.
Chromosome abnormality sample
Imatinib mesylate (Glivec) affects the BCR-ABL chimeric protein, that is made up of parts of two genes that fuse together in leukemias.
For cancer treatment there have been approved many different types of targeted therapy
Hormone therapy
It brakes down or stops the growth of hormone-sensitive tumors. Hormone therapy precludes own hormones formation or interferes with them, that doesn’t allow to hormone-dependent cells overgrowth. Hormone therapy has been approved for breast and prostate cancer.
Apoptosis inductors
Cause a controlled death of tumor cells that is called apoptosis.
Apoptosis is one of the procedure the body employs to eliminate unnecessary or abnormal cells, however, tumor cells have ways to elude it. Apoptosis inducers can evade these methods, causing malignant cell death.
Angiogenesis inhibitors
Inhibitors of angiogenesis disable the new blood vessels formation (angiogenesis) and so preclude tumor feeding.
The oxygen and nutrients for tumor growing are delivered in tumor by blood via vessels. Drugs that blocks angiogenesis can brake down and stop tumor growth. Certain targeted therapy blocks the activity of vascular endothelial growth factor (VEGF), a stimulator of new blood vessel formation. There are also angiogenesis inhibitors that target other molecules- stimulants the growth of new blood vessels.
Immunotherapy
Immunotherapy promotes destruction of cancer cells through immune system. Some types of immunotherapy are monoclonal antibodies that identify certain molecules on the surface of cancer cells. Linkage of a monoclonal antibody to a target molecule causes the damage of cells that produce that target molecule.
Some other monoclonal antibodies bind to specific immune cells for improving of cancer cells detection and elimination.
Monoclonal antibodies
Cancer cell death can be achieved by bringing toxic molecules with monoclonal antibodies. A toxic molecule such as a radioactive substance or a cytotoxic chemical, conjugated with antibody that links to its target cell is taken up by the cell, eventually destroying it . The toxin does not influence cells that lack a target for the antibody, that is, the overwhelming majority of cells in the organism.
Signal transduction inhibitors
Signal transduction inhibitors prevent the activity of molecules that are engaged in the procedure where a cell responds to external signals. When cell is constantly stimulated to continuous division and immortalization without a signal from external regulators (growth factor proteins) the process of transformation of normal cell to cancer cell occurs.
Gene expression modulators
Substances that change the function of gene expression regulator proteins in tumor cells, thus affecting their growth, development and division, are called gene expression modulators.
Search for a targeted therapy candidates
Some types of cancer already have a suitable molecular target in most patients, potentially making them candidates for targeted therapy. In particular, most patients with chronic myeloblastic leukemia develop a chimeric BCR-ABL gene, a target for the targeted drug Imatinib.
For other cancer types, the tumor tissue should be scrupulously examined for a suitable target identification. Targeted therapy prescription is limited to patients whose tumor has a particular gene alteration making a target.
In certain cases, patients are candidates for targeted therapy only if they fit special criteria (eg, disease recurrence, locally advanced, metastatic, or unresectable tumor). These criteria are established by the regulatory authority when approving indications for the prescription of a specific targeted therapy.
Targeted cancer therapy limitations
Targeted therapy has some limitations:
Probable development of resistance
After a while of therapy starting, the tumor may become resistant. Resistance can occur through two main mechanisms:
- The target itself modification (because of a new mutation appearance and/or artificial selection of a group of cancer cells with a resistant mutation). The targeted drug no longer works in this scenario.
- Cancer cells discover an alternative growth path that does not depend on the target of the targeted therapy applied.
For instance, the usage in combination two targeted medicine (BRAF and MEK inhibitors) in BRAF V600E-mutated melanoma brakes the progression of the disease and the resistance formation appreciably in comparison with the single drug application.
Another method is using targeted therapy combined with one or more traditional chemotherapy medicine.
For instance, targeted therapy with trastuzumab (Herceptin) combined with docetaxel, conventional chemotherapy medicine, for metastatic breast cancer with HER2/neu protein hyperexpression.
Complexity of drug development
Some of the detected targets have a complex structure and specific cellular regulation, making it hard to develop a drug.
An example of such a «target» is the proteins of the RAS family, elements of the signaling pathway of the same name.
At the moment, there is no inhibitor that is able to block these proteins, notwithstanding genetic disorders in the genes of the RAS family have been detected in ~25% of all cancers.
Approved targeted medicine in field of oncology
Cancer types and agents approved by the FDA
(some types of targeted therapies have been approved to treat more than one type of cancer):
Genetic testing for targeted therapy — What targeted drugs have been approved to treat certain types of cancer?