Because scientists call these specific molecules “molecular targets,” therapies that interfere with them are sometimes called “molecularly targeted drugs,” “molecularly targeted therapies ," or other similar names (see Question 1 ).
Targeted cancer therapies that have been approved for use in specific cancers include drugs that interfere with cell growth signaling or tumor blood vessel development, that promote the specific death of cancer cells, that stimulate the immune system to destroy specific cancer cells, and that deliver toxic drugs to cancer cells (see Questions 4 and 5 ).
The National Cancer Institute’s Molecular Targets Laboratory is working to identify and evaluate molecular targets (see Question 8 ).
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 involved in tumor growth and progression. Because scientists often call these molecules “molecular targets,” targeted cancer therapies are sometimes called “molecularly targeted drugs,” “molecularly targeted therapies,” or other similar names. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than other types of treatment, including chemotherapy and radiotherapy , and less harmful to normal cells.
Many targeted cancer therapies have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of specific types of cancer (see details in Questions 4 and 5 ). Others are being studied in clinical trials (research studies with people), and many more are in preclinical testing (research studies with animals).
Targeted cancer therapies are being studied for use alone, in combination with other targeted therapies, and in combination with other cancer treatments, such as chemotherapy.
How do targeted cancer therapies work?
Targeted cancer therapies interfere with cancer cell division (proliferation) and spread in different ways. Many of these therapies focus on proteins that are involved in cell signaling pathways, which form a complex communication system that governs basic cellular functions and activities, such as cell division, cell movement, how a cell responds to specific external stimuli, and even cell death. By blocking signals that tell cancer cells to grow and divide uncontrollably, targeted cancer therapies can help stop cancer progression and may induce cancer cell death through a process known as apoptosis . Other targeted therapies can cause cancer cell death directly, by specifically inducing apoptosis, or indirectly, by stimulating the immune system to recognize and destroy cancer cells and/or by delivering toxic substances to them.
The development of targeted therapies, therefore, requires the identification of good targets—that is, targets that are known to play a key role in cancer cell growth and survival. (It is for this reason that targeted therapies are often referred to as the product of “rational drug design.”)
For example, most cases of chronic myeloid leukemia (CML) are caused by the formation of a gene called BCR-ABL. This gene is formed when pieces of chromosome 9 and chromosome 22 break off and trade places. One of the changed chromosomes resulting from this switch contains part of the ABL gene from chromosome 9 coupled, or fused, to part of the BCR gene from chromosome 22. The protein normally produced by the ABL gene (Abl) is a signaling molecule that plays an important role in controlling cell proliferation and usually must interact with other signaling molecules to be active. However, Abl signaling is always active in the protein (Bcr-Abl) produced by the BCR-ABL fusion gene . This activity promotes the continuous proliferation of CML cells. Therefore, Bcr-Abl represents a good molecule to target.
How are targeted therapies developed?
Once a target has been identified, a therapy must be developed. Most targeted therapies are either small-molecule drugs or monoclonal antibodies . Small-molecule drugs are typically able to diffuse into cells and can act on targets that are found inside the cell. Most monoclonal antibodies usually cannot penetrate the cell’s plasma membrane and are directed against targets that are outside cells or on the cell surface.
Candidates for small-molecule drugs are usually identified in studies known as drug screens— laboratory tests that look at the effects of thousands of test compounds on a specific target, such as Bcr-Abl. The best candidates are then chemically modified to produce numerous closely related versions, and these are tested to identify the most effective and specific drugs.
Monoclonal antibodies, by contrast, are prepared first by immunizing animals (typically mice) with purified target molecules. The immunized animals will make many different types of antibodies against the target. Next, spleen cells, each of which makes only one type of antibody, are collected from the immunized animals and fused with myeloma cells. Cloning of these fusion cells results in cultures of cells that produce large amounts of a single type of antibody, or a monoclonal antibody. These antibodies are then tested to find the ones that react best with the target.
Before they can be used in humans, monoclonal antibodies are “humanized” by replacing as much of the nonhuman portion of the molecule as possible with human portions. This is done through genetic engineering. Humanizing is necessary to prevent the human immune system from recognizing the monoclonal antibody as “foreign” and destroying it before it has a chance to interact with and inactivate its target molecule.
What was the first target for targeted cancer therapy?
The first molecular target for targeted cancer therapy was the cellular receptor for the female sex hormoneestrogen , which many breast cancers require for growth. When estrogen binds to the estrogen receptor (ER) inside cells, the resulting hormone-receptor complex activates the expression of specific genes, including genes involved in cell growth and proliferation. Research has shown that interfering with estrogen’s ability to stimulate the growth of breast cancer cells that have these receptors (ER-positive breast cancer cells) is an effective treatment approach.
Several drugs that interfere with estrogen binding to the ER have been approved by the FDA for the treatment of ER-positive breast cancer. Drugs called selective estrogen receptor modulators ( SERMs ), including tamoxifen and toremifene (Fareston®) , bind to the ER and prevent estrogen binding. Another drug, fulvestrant (Faslodex®) , binds to the ER and promotes its destruction, thereby reducing ER levels inside cells.
Another class of targeted drugs that interfere with estrogen’s ability to promote the growth of ER-positive breast cancers is called aromatase inhibitors (AIs). The enzyme aromatase is necessary to produce estrogen in the body. Blocking the activity of aromatase lowers estrogen levels and inhibits the growth of cancers that need estrogen to grow. AIs are used mostly in women who have reached menopause because the ovaries of premenopausal women can produce enough aromatase to override the inhibition. Three AIs have been approved by the FDA for the treatment of ER-positive breast cancer: Anastrozole (Arimidex®) , exemestane (Aromasin®) , and letrozole (Femara®) .
What are some other targeted therapies?
Targeted cancer therapies have been developed that interfere with a variety of other cellular processes. FDA-approved targeted therapies are listed below:
Some targeted therapies block specific enzymes and growth factor receptors involved in cancer cell proliferation. These drugs are also called signal transduction inhibitors.
Trastuzumab (Herceptin®) is approved for the treatment of certain types of breast cancer. It is a monoclonal antibody that binds to the human epidermal growth factor receptor 2 (HER-2). HER-2, a receptor with tyrosine kinase activity, is expressed at high levels in some breast cancers and also some other types of cancer. The mechanism by which trastuzumab acts is not completely understood, but one likely possibility is that by binding to HER-2 on the surface of tumor cells that express high levels of HER-2, it prevents HER-2 from sending growth-promoting signals. Trastuzumab may have other effects as well, such as inducing the immune system to attack cells that express high levels of HER-2.
Lapatinib (Tykerb®) is approved for the treatment of certain types of advanced or metastatic breast cancer. This small-molecule drug inhibits several tyrosine kinases, including the tyrosine kinase activity of HER-2. Lapatinib treatment prevents HER-2 signals from activating cell growth.
Erlotinib (Tarceva®) is approved to treat metastatic non-small cell lung cancer and pancreatic cancer that cannot be removed by surgery or has metastasized. This small-molecule drug inhibits the tyrosine kinase activity of EGFR.
Panitumumab (Vectibix®) is approved to treat some patients with metastatic colon cancer. This monoclonal antibody attaches to EGFR and prevents it from sending growth signals.
Temsirolimus (Torisel®) is approved to treat patients with advanced renal cell carcinoma . This small-molecule drug is a specific inhibitor of a serine/threonine kinase called mTOR that is activated in tumor cells and stimulates their growth and proliferation.
Everolimus (Afinitor®) is approved to treat patients with advanced kidney cancer whose disease has progressed after treatment with other therapies. This small-molecule drug binds to a protein called immunophilin FK binding protein-12, forming a complex that in turn binds to and inhibits the mTOR kinase.
Other targeted therapies modify the function of proteins that regulate gene expression and other cellular functions.
Vorinostat (Zolinza®) is approved for the treatment of CTCL that has persisted, progressed, or recurred during or after treatment with other medicines. This small-molecule drug inhibits the activity of a group of enzymes called histone deacetylases (HDACs), which remove small chemical groups called acetyl groups from many different proteins, including proteins that regulate gene expression. By altering the acetylation of these proteins, HDAC inhibitors can induce tumor cell differentiation , cell cycle arrest, and apoptosis.
Bexarotene (Targretin®) is approved for the treatment of some patients with CTCL. This drug belongs to a class of compounds called retinoids , which are chemically related to vitamin A . Bexarotene binds selectively to, and thereby activates, retinoid X receptors. Once activated, these nuclear proteins act in concert with retinoic acid receptors to regulate the expression of genes that control cell growth, differentiation, survival, and death.
Some targeted therapies induce cancer cells to undergo apoptosis (cell death).
Bortezomib (Velcade®) is approved to treat some patients with multiple myeloma . It is also approved for the treatment of some patients with mantle cell lymphoma . Bortezomib causes cancer cells to die by interfering with the action of a large cellular structure called the proteasome, which degrades proteins. Proteasomes control the degradation of many proteins that regulate cell proliferation. By blocking this process, bortezomib causes cancer cells to die. Normal cells are affected too, but to a lesser extent.
Pralatrexate (Folotyn®) is approved for the treatment of some patients with peripheral T-cell lymphoma . Pralatrexate is an antifolate , which is a type of molecule that interferes with DNA synthesis. Other antifolates, such as methotrexate , are not considered targeted therapies because they interfere with DNA synthesis in all dividing cells. However, pralatrexate appears to selectively accumulate in cells that express RFC-1, a protein that may be overexpressed by some cancer cells.
Other targeted therapies block the growth of blood vessels to tumors ( angiogenesis ). To grow beyond a certain size, tumors must obtain a blood supply to get the oxygen and nutrients needed for continued growth. Treatments that interfere with angiogenesis may block tumor growth.
Sorafenib (Nexavar®) is a small-molecule inhibitor of tyrosine kinases that is approved for the treatment of advanced renal cell carcinoma and some cases of hepatocellular carcinoma . One of the kinases that sorafenib inhibits is involved in the signaling pathway that is initiated when VEGF binds to its receptors. As a result, new blood vessel development is halted. Sorafenib also blocks an enzyme that is involved in cell growth and division.
Sunitinib (Sutent®) is another small-molecule tyrosine kinase inhibitor that is approved for the treatment of patients with metastatic renal cell carcinoma or gastrointestinal stromal tumor that is not responding to imatinib . It blocks kinases involved in VEGF signaling, thereby inhibiting angiogenesis and cell proliferation.
Ofatumumab (Arzerra®) is approved for the treatment of some patients with chronic lymphocytic leukemia (CLL) that does not respond to treatment with fludarabine and alemtuzumab. This monoclonal antibody is directed against the B-cell CD20 cell surface antigen .
Another class of targeted therapies includes monoclonal antibodies that deliver toxic molecules to cancer cells specifically.
Tositumomab and 131I-tositumomab (Bexxar®) is approved to treat certain types of B-cell non-Hodgkin lymphoma. It is a mixture of monoclonal antibodies that recognize the CD20 molecule. Some of the antibodies in the mixture are linked to a radioactive substance called iodine -131. The 131I- tositumomab component delivers radioactive energy to CD20-expressing B cells specifically, reducing collateral damage to normal cells of the type that is seen with traditional radiotherapy. In addition, the binding of tositumomab to the CD20-expressing B cells triggers the immune system to destroy these cells.
Denileukin diftitox (Ontak®) is approved for the treatment of some patients with CTCL. Denileukin diftitox consists of interleukin-2 (IL-2) protein sequences fused to diphtheria toxin. The drug binds to cell surface IL-2 receptors, which are found on certain immune cells and some cancer cells, directing the cytotoxic action of the diphtheria toxin to these cells.
Cancer vaccines and gene therapy are often considered to be targeted therapies because they interfere with the growth of specific cancer cells. Information about these treatments can be found in the following National Cancer Institute (NCI) fact sheets, which are available on the Internet, or by calling NCI’s Cancer Information Service (CIS) (see below):
What impact will targeted therapies have on cancer treatment?
Targeted cancer therapies give doctors a better way to tailor cancer treatment, especially when a target is present in some but not all tumors of a particular type, as is the case for HER-2. Eventually, treatments may be individualized based on the unique set of molecular targets produced by the patient’s tumor. Targeted cancer therapies also hold the promise of being more selective for cancer cells than normal cells, thus harming fewer normal cells, reducing side effects , and improving quality of life .
Nevertheless, targeted therapies have some limitations. Chief among these is the potential for cells to develop resistance to them. In some patients who have developed resistance to imatinib, for example, a mutation in the BCR-ABL gene has arisen that changes the shape of the protein so that it no longer binds this drug as well. In most cases, another targeted therapy that could overcome this resistance is not available. It is for this reason that targeted therapies may work best in combination, either with other targeted therapies or with more traditional therapies.
Where can I find information about clinical trials of targeted therapies?
The list below includes FDA-approved drugs that are being studied in active clinical trials of targeted therapies. If you are viewing this fact sheet on NCI’s Web site ( http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted ), the drug names are links to search results for trials in NCI's clinical trials database. This database can also be searched on NCI’s Web site by visiting http://www.cancer.gov/clinicaltrials/search on the Internet. For information about how to search the database, see “Help Using the NCI Clinical Trials Search Form” at http://www.cancer.gov/clinicaltrials/search-form-help on the Internet. The database includes all NCI-funded clinical trials and many other studies conducted by investigators at hospitals and medical centers in the United States and other countries around the world.
NCI’s Molecular Targets Laboratory (MTL), part of NCI’s Center for Cancer Research (CCR), is working to identify and evaluate molecular targets that may be candidates for drug development. The initial goal of the MTL is to facilitate the discovery of compounds that may serve as bioprobes for functional genomics , proteomics , and molecular target validation research, as well as leads or candidates for drug development. The MTL’s Web site is located at https://ccrod.cancer.gov/confluence/display/CCRMTDPBeu/Introduction+to+MTL on the Internet.
NCI’s Chemical Biology Consortium (CBC) will facilitate the discovery and development of new agents to treat cancer. The CBC is part of the NCI Experimental Therapeutics Program, which is a collaborative effort of CCR and NCI’s Division of Cancer Treatment and Diagnosis. More information about the CBC can be found at http://dctd.cancer.gov/CurrentResearch/ChemicalBioConsortium.htm on the Internet.