Targeted Cancer Therapies Fact Sheet - National Cancer Institute
`
`Targeted Cancer Therapies
`
`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).
`
`• • •
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`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).
`
`How are targets for targeted cancer therapies identified?
`
`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. (It is for this reason that targeted therapies are sometimes referred
`to as the product of "rational" drug design.)    
`
`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.
`
`Another approach to identify potential targets is to determine whether cancer cells produce mutant (altered)
`proteins that drive cancer progression. For example, the cell growth signaling protein BRAF is present in an
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`Targeted Cancer Therapies Fact Sheet - National Cancer Institute
`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 that contains this
`altered BRAF protein.
`
`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. For example, imatinib mesylate (Gleevec®) targets
`the BCR-ABL fusion protein, which is made from pieces of two genes that get joined together in some leukemia
`cells and promotes the growth of leukemic cells.
`
`How are 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. For example, a targeted therapy could
`reduce the activity of the target or prevent it from binding to a receptor that it normally activates, among other
`possible mechanisms.
`
`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.
`
`Candidate small molecules are usually identified in what are known as "high-throughput screens," in which the
`effects of thousands of test compounds on a specific target protein are examined. Compounds that affect the
`target (sometimes called "lead compounds") 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.
`
`Monoclonal antibodies are developed by injecting animals (usually mice) 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.
`
`Before monoclonal antibodies are used in humans, they are "humanized" by replacing as much of the mouse
`antibody molecule as possible with corresponding portions of human antibodies. 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 bind to its target protein. Humanization is not an issue for small-molecule compounds
`because they are not typically recognized by the body as foreign.
`
`What types of targeted therapies are available?
`
`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.
`
`•
`
`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
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`Targeted Cancer Therapies Fact Sheet - National Cancer Institute
`with the action of the hormones. Hormone therapies have been approved for both breast cancer and
`prostate cancer.
`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 through a series of biochemical reactions that
`ultimately produce the appropriate response(s). 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.
`Gene expression modulators modify the function of proteins that play a role in controlling gene
`expression.
`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.
`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 molecules that stimulate new blood vessel growth.
`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.
`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 a
`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.
`
`•
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`• •
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`•
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`•
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`•
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`Cancer vaccines and gene therapy are sometimes considered targeted therapies because they interfere with
`the growth of specific cancer cells. Information about cancer vaccines can be found in the NCI fact sheet
`Biological Therapies for Cancer.
`
`How is it determined whether a patient is a candidate for targeted
`therapy?
`
`For some types of cancer, most 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.
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`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 (1).
`
`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 (2).
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`Similarly, patients who develop high blood pressure while being treated with the angiogenesis inhibitor
`bevacizumab generally have had better outcomes (3).
`
`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 (4).
`
`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):
`
`Adenocarcinoma of the stomach or gastroesophageal junction: Trastuzumab (Herceptin®), ramucirumab
`(Cyramza®)
`
`Bladder cancer: Atezolizumab (Tecentriq™), nivolumab (Opdivo®), durvalumab (Imfinzi™), avelumab
`(Bavencio®), pembrolizumab (Keytruda®)
`
`Brain cancer: Bevacizumab (Avastin®), everolimus (Afinitor®)
`
`Breast cancer: Everolimus (Afinitor®), tamoxifen (Nolvadex), toremifene (Fareston®), Trastuzumab
`(Herceptin®), fulvestrant (Faslodex®), anastrozole (Arimidex®), exemestane (Aromasin®), lapatinib (Tykerb®),
`letrozole (Femara®), pertuzumab (Perjeta®), ado-trastuzumab emtansine (Kadcyla®), palbociclib (Ibrance®),
`ribociclib (Kisqali®), neratinib maleate (Nerlynx™), abemaciclib (Verzenio™), olaparib (Lynparza™)
`
`Cervical cancer: Bevacizumab (Avastin®), pembrolizumab (Keytruda®)
`
`Colorectal cancer: Cetuximab (Erbitux®), panitumumab (Vectibix®), bevacizumab (Avastin®), ziv-aflibercept
`(Zaltrap®), regorafenib (Stivarga®), ramucirumab (Cyramza®), nivolumab (Opdivo®), ipilimumab (Yervoy®)
`
`Dermatofibrosarcoma protuberans: Imatinib mesylate (Gleevec®)
`
`Endocrine/neuroendocrine tumors: Lanreotide acetate (Somatuline® Depot), avelumab (Bavencio®), lutetium
`Lu 177-dotatate (Lutathera®), iobenguane I 131 (Azedra®)
`
`Head and neck cancer: Cetuximab (Erbitux®), pembrolizumab (Keytruda®), nivolumab (Opdivo®)
`
`Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec®), sunitinib (Sutent®), regorafenib (Stivarga®)
`
`Giant cell tumor of the bone: Denosumab (Xgeva®)
`
`Kidney cancer: Bevacizumab (Avastin®), sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®),
`temsirolimus (Torisel®), everolimus (Afinitor®), axitinib (Inlyta®), nivolumab (Opdivo®), cabozantinib
`(Cabometyx™), lenvatinib mesylate (Lenvima®), ipilimumab (Yervoy®)
`
`Leukemia: Tretinoin (Vesanoid®), imatinib mesylate (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®),
`bosutinib (Bosulif®), rituximab (Rituxan®), alemtuzumab (Campath®), ofatumumab (Arzerra®), obinutuzumab
`(Gazyva®), ibrutinib (Imbruvica®), idelalisib (Zydelig®), blinatumomab (Blincyto®), venetoclax (Venclexta™),
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`ponatinib hydrochloride (Iclusig®), midostaurin (Rydapt®), enasidenib mesylate (Idhifa®), inotuzumab
`ozogamicin (Besponsa®), tisagenlecleucel (Kymriah®), gemtuzumab ozogamicin (Mylotarg™), rituximab and
`hyaluronidase human (Rituxan Hycela™), ivosidenib (Tibsovo®)
`
`Liver cancer: Sorafenib (Nexavar®), regorafenib (Stivarga®), nivolumab (Opdivo®), lenvatinib mesylate
`(Lenvima®)
`
`Lung cancer: Bevacizumab (Avastin®), crizotinib (Xalkori®), erlotinib (Tarceva®), gefitinib (Iressa®), afatinib
`dimaleate (Gilotrif®), ceritinib (LDK378/Zykadia™), ramucirumab (Cyramza®), nivolumab (Opdivo®),
`pembrolizumab (Keytruda®), osimertinib (Tagrisso™), necitumumab (Portrazza™), alectinib (Alecensa®),
`atezolizumab (Tecentriq™), brigatinib (Alunbrig™), trametinib (Mekinist®), dabrafenib (Tafinlar®),
`durvalumab (Imfinzi™)
`
`Lymphoma: Ibritumomab tiuxetan (Zevalin®), denileukin diftitox (Ontak®), brentuximab vedotin (Adcetris®),
`rituximab (Rituxan®), vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Targretin®), bortezomib
`(Velcade®), pralatrexate (Folotyn®), ibrutinib (Imbruvica®), siltuximab (Sylvant®), idelalisib (Zydelig®),
`belinostat (Beleodaq®), obinutuzumab (Gazyva®), nivolumab (Opdivo®), pembrolizumab (Keytruda®),
`rituximab and hyaluronidase human (Rituxan Hycela™), copanlisib hydrochloride (Aliqopa™), axicabtagene
`ciloleucel (Yescarta™), acalabrutinib (Calquence®), tisagenlecleucel (Kymriah®), venetoclax (Venclexta™),
`mogamulizumab-kpkc (Poteligeo®)
`
`Microsatellite instability-high or mismatch repair-deficient solid tumors: Pembrolizumab (Keytruda®)
`
`Multiple myeloma: Bortezomib (Velcade®), carfilzomib (Kyprolis®), panobinostat (Farydak®), daratumumab
`(Darzalex™), ixazomib citrate (Ninlaro®), elotuzumab (Empliciti™)
`
`Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec®), ruxolitinib phosphate (Jakafi®)
`
`Neuroblastoma: Dinutuximab (Unituxin™)
`
`Ovarian epithelial/fallopian tube/primary peritoneal cancers: Bevacizumab (Avastin®), olaparib
`(Lynparza™), rucaparib camsylate (Rubraca™), niraparib tosylate monohydrate (Zejula™)
`
`Pancreatic cancer: Erlotinib (Tarceva®), everolimus (Afinitor®), sunitinib (Sutent®)
`
`Prostate cancer: Cabazitaxel (Jevtana®), enzalutamide (Xtandi®), abiraterone acetate (Zytiga®), radium 223
`dichloride (Xofigo®), apalutamide (Erleada™)
`
`Skin cancer: Vismodegib (Erivedge®), sonidegib (Odomzo®), ipilimumab (Yervoy®), vemurafenib (Zelboraf®),
`trametinib (Mekinist®), dabrafenib (Tafinlar®), pembrolizumab (Keytruda®), nivolumab (Opdivo®), cobimetinib
`(Cotellic™), alitretinoin (Panretin®), avelumab (Bavencio®), encorafenib (Braftovi™), binimetinib (Mektovi®)
`
`Soft tissue sarcoma: Pazopanib (Votrient®), olaratumab (Lartruvo™), alitretinoin (Panretin®)
`
`Stomach cancer: Pembrolizumab (Keytruda®)
`
`Systemic mastocytosis: Imatinib mesylate (Gleevec®), midostaurin (Rydapt®)
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`Thyroid cancer: Cabozantinib (Cometriq®), vandetanib (Caprelsa®), sorafenib (Nexavar®), lenvatinib mesylate
`(Lenvima®), trametinib (Mekinist®), dabrafenib (Tafinlar®)
`
`Where can I find information about clinical trials of targeted therapies?
`
`Both FDA-approved and experimental targeted therapies for specific types of cancer are being studied in clinical
`trials. Descriptions of ongoing clinical trials that are testing types of targeted therapies in cancer patients can be
`accessed by searching NCI’s list of cancer clinical trials. NCI’s list of cancer clinical trials includes all NCI-
`supported clinical trials that are taking place across the United States and Canada, including the NIH Clinical
`Center in Bethesda, MD. For information about other ways to search the list, see Help Finding NCI-Supported
`Clinical Trials.
`
`Alternatively, call the NCI Contact Center at 1-800-4-CANCER (1-800-422-6237) for information about clinical trials
`of targeted therapies.
`
`Selected References
`1. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600
`mutations. New England Journal of Medicine 2012; 367(18):1694-1703. [PubMed Abstract]
`2. Petrelli F, Borgonovo K, Cabiddu M, Lonati V, Barni S. Relationship between skin rash and outcome in non-
`small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: A literature-based meta-
`analysis of 24 trials. Lung Cancer 2012; 78(1):8-15. [PubMed Abstract]
`3. Cai J, Ma H, Huang F, et al. Correlation of bevacizumab-induced hypertension and outcomes of metastatic
`colorectal cancer patients treated with bevacizumab: a systematic review and meta-analysis. World Journal
`of Surgical Oncology 2013; 11:306. [PubMed Abstract]
`4. Gore L, DeGregori J, Porter CC. Targeting developmental pathways in children with cancer: what price
`success? Lancet Oncology 2013; 4(2):e70-78. [PubMed Abstract]
`
`Related Resources
`Angiogenesis Inhibitors
`Biological Therapies for Cancer
`Hormone Therapy for Breast Cancer
`Hormone Therapy for Prostate Cancer
`The RAS Initiative
`
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