Targeted Therapies for Cancer

What are Targeted Cancer Therapies?

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,” “precision medicines,” or similar names.

Targeted therapies differ from standard chemotherapy in several ways

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.

Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells.

Targeted therapies are often cytostatic (that is, they block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (that is, they kill tumor cells).

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 by the Food and Drug Administration (FDA) to treat specific types of cancer. Others are being studied in clinical trials (research studies with people), and many more are in preclinical testing (research studies with animals).

Types of Targeted Therapies

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. Other monoclonal antibodies bind to certain immune cells to help these cells better kill cancer cells.

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.

Gene Expression Modulators modify the funcation of proteins that play a role in controlling gene expression.

Caner Vaccines and Gene Therapy are sometimes considered targeted therapies because they interfere with the growth of specific cancer cells.

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. During this process, once a cell has received a specific signal, the signal is relayed within the cell throught a series of biochemial reactions that ultimately produce the appropriate response(s). In some cancers, teh malignant cells are stimulated to adivide continuously without being promoted to do so by external growth factors. Signal transduction inhibitors interfere with this inappropriate signaling. 

Angiogenesis Inhibitors block the growth of new blood vessels to tumors (a process called tumor angiogenesis). A blood supply is necessary for tumors to grow beyond a certain size because blood provides the oxygen and nutrients that tumors need for continued growth. Treatments that interfere with angiogenesis may block tumor growth. some targeted therapies that inhibit angiogenesis interfere with the action of vascular endothelial growth factor (VEGF), a substance that stimulates new blood vessel formation. Other angiogenesis inhibitors target other moledules that stimulate new blood vessel growth. 

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 – such as radioactive substance or a poisonous chemical – is taken up by the cell, ultimately killing that cell. The toxin will not affect cells that lack the target for the antibody – i.e. the vast majority of cells in the body.

How is it determined whether a patient is a candidate for targeted therapy?

Some cancer cells express certain receptors and targets on their surface. Some patients with that cancer will have an appropriate target for a particular targeted therapy and, thus, will be candidates to be treated with that therapy. CML is an example: most patients have the BCR-ABL fusion gene. For other cancer types, however, a patient’s tumor tissue must be tested to determine whether or not an appropriate target is present. The use of a targeted therapy may be restricted to patients whose tumor has a specific gene mutation that codes for the target; patients who do not have the mutation would not be candidates because the therapy would have nothing to target.

Sometimes, a patient is a candidate for a targeted therapy only if he or she meets specific criteria (for example, their cancer did not respond to other therapies, has spread, or is inoperable). These criteria are set by the FDA when it approves a specific targeted therapy.

What are the limitations of targeted cancer therapies?

Targeted therapies do have some limitations. One is that cancer cells can become resistant to them. Resistance can occur in two ways: the target itself changes through mutation so that the targeted therapy no longer interacts well with it, and/or the tumor finds a new pathway to achieve tumor growth that does not depend on the target.

For this reason, targeted therapies may work best in combination. For example, a recent study found that using two therapies that target different parts of the cell signaling pathway that is altered in melanoma by the BRAF V600E mutation slowed the development of resistance and disease progression to a greater extent  than using just one targeted therapy.    

Another approach is to use a targeted therapy in combination with one or more traditional chemotherapy drugs. For example, the targeted therapy trastuzumab (Herceptin®) has been used in combination with docetaxel, a traditional chemotherapy drug, to treat women with metastatic breast cancer that overexpresses the protein HER2/neu.

Another limitation of targeted therapy at present is that drugs for some identified targets are difficult to develop because of the target’s structure and/or the way its function is regulated in the cell. One example is Ras, a signaling protein that is mutated in as many as one-quarter of all cancers (and in the majority of certain cancer types, such as pancreatic cancer). To date, it has not been possible to develop inhibitors of Ras signaling with existing drug development technologies. However, promising new approaches are offering hope that this limitation can soon be overcome.

What are the side effects of targeted cancer therapies?

Scientists had expected that targeted cancer therapies would be less toxic than traditional chemotherapy drugs because cancer cells are more dependent on the targets than are normal cells. However, targeted cancer therapies can have substantial side effects.

The most common side effects seen with targeted therapies are diarrhea and liver problems, such as hepatitis and elevated liver enzymes.  Other side effects seen with targeted therapies include:

  • Skin problems (acneiform rash, dry skin, nail changes, hair depigmentation)
  • Problems with blood clotting and wound healing
  • High blood pressure
  • Gastrointestinal perforation (a rare side effect of some targeted therapies)

Certain side effects of some targeted therapies have been linked to better patient outcomes. For example, patients who develop acneiform rash (skin eruptions that resemble acne) while being treated with the signal transduction inhibitors erlotinib (Tarceva®) or gefitinib (Iressa®), both of which target the epidermal growth factor receptor, have tended to respond better to these drugs than patients who do not develop the rash. Similarly, patients who develop high blood pressure while being treated with the angiogenesis inhibitor bevacizumab generally have had better outcomes.

The few targeted therapies that are approved for use in children can have different side effects in children than in adults, including immunosuppression and impaired sperm production.

What targeted therapies have been approved for specific types of cancer?

The FDA has approved targeted therapies for the treatment of some patients with the following types of cancer (some targeted therapies have been approved to treat more than one type of cancer):

Bladder cancer: Brain cancer: Breast cancer: Cervical cancer: Colorectal cancer: Dermatofibrosarcoma protuberans: Endocrine/neuroendocrine tumors: Endometrial cancer: Esophageal cancer: Head and neck cancer: Gastrointestinal stromal tumor: Giant cell tumor of the bone: Kidney cancer: Leukemia: Liver cancer: Lung cancer: Lymphoma: Multiple myeloma: Microsatellite instability-high or mismatch repair-deficient solid tumors: Myelodysplastic/myeloproliferative disorders: Neuroblastoma: Ovarian epithelial/fallopian tube/primary peritoneal cancers: Pancreatic cancer: Prostate cancer: Skin cancer: Soft tissue sarcoma: Solid tumors with an NTRK gene fusion: Stomach (gastric) cancer: Systemic mastocytosis: Thyroid cancer: