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Targeted therapy

Targeted therapy overview

   Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules (molecular targets) that are involved in the growth, progression, and spread of cancer. Targeted cancer therapies are sometimes called molecularly targeted drugs, molecularly targeted therapies, or precision medicines. Targeted therapies differ from standard chemotherapy in several ways:

1) Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells.
2) Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells.
3) Targeted therapies are often cytostatic (block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (kill tumor cells).
4) Targeted therapies are currently the focus of much anticancer drug development. They are a cornerstone of precision medicine, a form of medicine that uses information about a person’s genes and proteins to prevent, diagnose, and treat disease. Many targeted cancer therapies have been approved to treat specific types of cancer.

Targets for targeted cancer therapies

The development of targeted therapies requires the identification of good targets—that is, targets that play a key role in cancer cell growth and survival.
1) Compare the amounts of individual proteins
   One approach to identify potential targets is to compare the amounts of individual proteins in cancer cells with those in normal cells. Proteins that are present in cancer cells but not normal cells or that are more abundant in cancer cells would be potential targets, especially if they are known to be involved in cell growth or survival. An example of such a differentially expressed target is the human epidermal growth factor receptor 2 protein (HER-2). HER-2 is expressed at high levels on the surface of some cancer cells. Several targeted therapies are directed against HER-2, including trastuzumab (Herceptin), which is approved to treat certain breast and stomach cancers that overexpress HER-2.
2) Check cancer cells produce mutant proteins
   Another approach to identify potential targets is to determine whether cancer cells produce mutant proteins that drive cancer progression. For example, the cell growth signaling protein BRAF is present in an altered form in many melanomas. This mutant form of the BRAF protein is approved to treat patients with inoperable or metastatic melanoma that contains this altered BRAF protein.
3) Fusion proteins
   Researchers also look for abnormalities in chromosomes that are present in cancer cells but not in normal cells. Sometimes these chromosome abnormalities result in the creation of a fusion gene (a gene that incorporates parts of two different genes) whose product, called a fusion protein, may drive cancer development. Such fusion proteins are potential targets for targeted cancer therapies.

Targeted therapies developed

   Once a candidate target has been identified, the next step is to develop a therapy that affects the target in a way that interferes with its ability to promote cancer cell growth or survival. Most targeted therapies are either small molecules or monoclonal antibodies. Small-molecule compounds are typically developed for targets that are located inside the cell because such agents are able to enter cells relatively easily. Monoclonal antibodies are relatively large and generally cannot enter cells, so they are used only for targets that are outside cells or on the cell surface.
1) Small molecules
   Candidate small molecules are usually identified in what are known as "high-throughput screens". Compounds that affect the target are then chemically modified to produce numerous closely related versions of the lead compound. These related compounds are then tested to determine which are most effective and have the fewest effects on nontarget molecules.
2) Monoclonal antibodies
   Monoclonal antibodies are developed by injecting animals with purified target proteins, causing the animals to make many different types of antibodies against the target. These antibodies are then tested to find the ones that bind best to the target without binding to nontarget proteins.

Available targeted therapies


   Many different targeted therapies have been approved for use in cancer treatment. These therapies include hormone therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies, and toxin delivery molecules.
1) Hormone therapies slow or stop the growth of hormone-sensitive tumors, which require certain hormones to grow. Hormone therapies act by preventing the body from producing the hormones or by interfering with the action of the hormones. Hormone therapies have been approved for both breast cancer and prostate cancer.
2) Signal transduction inhibitors block the activities of molecules that participate in signal transduction, the process by which a cell responds to signals from its environment. In some cancers, the malignant cells are stimulated to divide continuously without being prompted to do so by external growth factors. Signal transduction inhibitors interfere with this inappropriate signaling.
3) Gene expression modulators modify the function of proteins that play a role in controlling gene expression.
4) Apoptosis inducers cause cancer cells to undergo a process of controlled cell death called apoptosis. Apoptosis is one method the body uses to get rid of unneeded or abnormal cells, but cancer cells have strategies to avoid apoptosis. Apoptosis inducers can get around these strategies to cause the death of cancer cells.
5) Angiogenesis inhibitors block the growth of new blood vessels to tumors. Some targeted therapies that inhibit angiogenesis interfere with the action of vascular endothelial growth factor (VEGF), a substance that stimulates new blood vessel formation.

6) Immunotherapies trigger the immune system to destroy cancer cells. Some immunotherapies are monoclonal antibodies that recognize specific molecules on the surface of cancer cells. Binding of the monoclonal antibody to the target molecule results in the immune destruction of cells that express that target molecule.
7) Monoclonal antibodies that deliver toxic molecules can cause the death of cancer cells specifically. Once the antibody has bound to its target cell, the toxic molecule that is linked to the antibody is taken up by the cell, ultimately killing that cell. The toxin will not affect the vast majority of cells in the body.
8) Cancer vaccines and gene therapy are sometimes considered targeted therapies because they interfere with the growth of specific cancer cells.