Targeted therapy in cancer
Targeted cancer therapy is represented by drugs or substances that interfere with specific molecules involved in cancer cell growth and survival.
Traditional chemotherapy drugs as opposed to targeted therapy that acts against all active cells divide. Targeted cancer therapy that has been approved for use in cancer include agents that prevent cell growth signaling agents that interfere with the development of tumor blood vessels, promotes the death of cancer cells, stimulates the immune system to destroy cancer cells, and releases toxic drugs in cancer cells.
Targeted therapies are anticancer drugs or other substances that block the growth and dissemination of cancer by interfering with specific molecules (“molecular targets”) that are involved in the growth, progression and dissemination of cancer. The targeting of anticancer therapies are also called molecular target drug.
Targeted therapy acts on specific molecular targets that are associated with cancer, while most standard chemotherapy works on all dividing normal cells and cancer cells. Therapy is often targeted cytostatic (that block the tumor cell proliferation, while most standard chemotherapy drugs are cytotoxic (cripples tumor cells). Targeted therapy is the foundation of precision medicine (personalized medicine) a form of medicine that uses information about genes and proteins person to prevent, diagnose and tartaric disease.
Identification of targeted anticancer therapies
The advent of targeted therapies requires identification of appropriate targets ie targets that play a key role in the growth and survival of cancer cells. One way to identify potential targets is to compare the amounts of individual proteins in cancer cells with normal cells. The proteins that are present in cancer cells but not in normal cells or cancerous cells are more abundant as potential targets would rot especially if they are known to be involved in the growth and survival of cancer cells. An example of a differentially expressed target is the epidermal growth factor receptor (HER-2). Her-2 is expressed at high levels on the surface of cancer cells. Several targeted therapies are directed against HER-2, including trastuzumab (Hercep-tin) which is approved for treatment of breast and stomach cancer overexpressing HER-2.
Another way to identify potential targets is to determine if cancer cells produce proteins mutated (changed) that trigger cancer progression. For example cell growth signaling protein BRAF is a BRAF V600E known as altered form. In melanomas, vemurafenib (Zelboraf) targets this BRAF mutant form of the protein and is approved for treatment of patients with unresectable or metastatic melanoma containing mutant form of BRAF (V600E BRAF).
Research of chromosomal abnormalities that are present in cancer cells but not in normal cells is another way to identify potential targets. Sometimes these chromosomal abnormalities cause a fusion gene (a gene that incorporates parts of two different genes) whose product called fusion protein can trigger cancer. Such fusion proteins are targeted anticancer potential targets for therapies. For example imatinib mesylate (Glivec) targets BCR-ABL fusion protein that is composed of parts of two genes that joined in some leukemia cells and promotes the growth of leukemia cells.
Devices targeted therapies
Once a candidate has been identified target, the next step is to develop a therapy that affects the target in a way that alters its capacitance to promote growth and survival of cancer cells. For example, a targeted therapy could reduce or prevent its binding target activity of a receptor that normally activates.
Most targeted therapies are either small molecules or monoclonal antibodies. Develops small molecules to target localized within the cell because these agents are able to enter cells quite easily. Monoclonal antibodies are relatively large and generally cannot enter cells, so monoclonal antibodies are used only for targets that are outside cells or on the cell surface.
Candidates for small molecules are detected by examining the effects of thousands of compounds to test on a specific target protein. Compounds that affect the target (sometimes called key compounds) are then chemically modified to produce numerous closely related versions of the title compound. These related compounds are then screened to determine which are most effective and have the fewest effects on non-target cells.
Development of monoclonal antibodies is done by injecting animals (usually mice) with specific target proteins, forcing the animal to produce several different types of antibodies to target. These antibodies are then screened to find one that best binds to target protein without binding to non-target.
Before being used on humans, the monoclonal antibodies are “humanized” by replacing as many animals of antibody molecules corresponding to portions of human antibodies. Humanization is needed to prevent recognition of monoclonal antibody as “foreign” by the human immune system would destroy it before bind to the target protein. Humanization is not a problem for small molecule compounds because they normally are not recognized by the body as foreign.
Types of Targeted Therapies
Hormone therapy slows or stops the growth of hormonally sensitive tumors, which require certain growth hormones. Hormone therapy works by blocking the body to produce hormones by interfering with the action of hormones. Hormone therapy has been approved for breast and prostate cancer.
Signal transduction inhibitors block the activity of molecules which participate in signal transduction, a process by which a cell responds to its microenvironment surrounding the signals. During this process, once the cells received a signal into the cell specific signal is relayed through a series of biochemical reactions that ultimately produce the appropriate response. In some cancers, malignant cells are stimulated to divide continuously without being stimulated by external growth factors. Inhibition of signal transduction interferes with this signaling inadequate.
Gene expression modulators alter the function of proteins that play a role in controlling gene expression.
Inducers of apoptosis cause cancer cells to undergo a process of controlled cell death, a process called apoptosis. Apoptosis is a method that the body uses to get rid of unnecessary or abnormal cells, even cancer cells to avoid apoptosis strategies. Inducers of apoptosis may act around these strategies to induce cancer cell death.
Angiogenesis inhibitors block the growth of new blood vessels to the tumor (a process called tumor angiogenesis). Tumor blood supply is needed to grow beyond a certain size Since there blood supply oxygen and nutrients that the tumor needs for continued growth. Treatments interfering with angiogenesis may block tumor growth. Some targeted therapies that inhibit angiogenesis interferes with the action vasculoendotelial growth factor (VEGF), a substance that stimulates new blood vessel formation. Other angiogenesis inhibitors target other molecules that stimulate the growth of new blood vessels.
Immunotherapy triggers the immune system to destroy cancer cells. Some immunotherapy are monoclonal antibodies which recognize specific molecules on the surface of cancer cells. The binding of monoclonal antibodies to target molecules results in destruction of the immune cells that express the target molecule. Other monoclonal antibodies bind to specific immune cells to help these cells to destroy cancer cells better.
Monoclonal antibodies that release toxic molecules can determine specific cancer cell death. Once the monoclonal antibody has bound to the target cell, toxic molecule is bound to the antibody, for example a radioactive substance or a chemical toxin is taken up by the cell-determining cell destruction. The toxin does not affect cells lacking the target for antibodies, ie the vast majority of cells in the body.
Choosing patients for targeted therapy
For some cancers, the majority of cancer patients will have a suitable target for a particular targeted therapy. Chronic myeloid leukemia (CML) is an example: most patients have BCR-ABL fusion gene. For other types of cancer tumor tissue to be tested to determine whether there is an appropriate target. Using targeted therapy should be restricted to patients whose tumor has a specific gene mutation that encodes the target. Patients who are not candidates because they mutation terappia will have no target.
Limits of targeted therapy
One limit is that cancer cells can be resistant to targeted therapy. Resistance can occur in two ways: target is modified through mutations so that targeted therapy does not interact well with the target/tumor and finds a new way to get tumor growth that does not depend of the target. This is why targeted therapies work well in combination. For example, a recent study found that the use of the two therapies that target different parts of the signaling pathway that is altered by mutation BRAF V600E melanoma, has slowed the development of resistance and progression of the disease at a greater degree than using only targeted therapy .
Another way is to use targeted therapy in combination with one or more traditional chemotherapy drugs. For example targeted therapy trastuzumab (hercep-tin) was used in combination with docetaxel to treat women with metastatic breast cancer overexpressing HER 2 neu protein.
Another limitation is that the targeted therapy drugs for some targets are difficult to develop because the structure or pathway of the target is regulated within the cell. One example is the Ras signaling a protein which is mutated in 25% of all cancers (and in the majority of certain types of cancer, for example pancreatic cancer). Until now it has not been possible to develop inhibitors of the Ras signaling with current techniques.
Side effects of targeted therapy
It is expected that targeted therapy to be less toxic than traditional chemotherapy because the cancer cells are more dependent on targets than are normal cells. However biomarker guided therapy could have substantial side effects.
The most common side effects seen with targeted therapy are diarrhea and hepatitis and liver problems for example enzymes increased.
Other side effects include:
– Cutaneous problems (acne-type rash, dry skin, nail changes, hair depigmentation)
– Clotting dissorders, wound healing problems
– Gastrointestinal perforation
Some side effects have been linked to better patient evolution. For example, patients who develop ane-type rash during treatment with Tarceva or Gefitinib, both targeting the epidermal growth factor receptor tended to respond better to these drugs than patients who did not develop rash. Similar patients who develop hypertension after treatment with the angiogenesis inhibitor, Bervacizumab in general had better evolution.
Some targeted therapies that are approved for use in children may have different side effects in children than adults, including immunosuppression and low production of sperm.
Targeted therapies depending on the type of cancer
Junction adenocarcinoma of the stomach or esogastric: Trastuzumab (Hercep-tin), ramucirumab (Cyramza).
Basal cell carcinoma: vismodegib (Erivedge)
Brain Cancer: Bevacvizumab (Avastin), everolimus (Afinitor)
Breast Cancer: Trastuzumab (Hercep-tin, lapatinib (TYKERB), pertuzumab (perjeta), trastuzumab emtansine-ado (kadcyla), tamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestane.
Cervical Cancer: bevacizumab (Avastin)
Colorectal Cancer: Cetuximab (Erbitux), panitumumab (Vectibix) bevacizumab (Avastin), Ziv-aflibercept (zaltrap) regorafenib (stivarga).
Dermatofibrosarcoma protuberans: imatinib mesylate (Glivec)
Neuroendocrine tumors: Lanreotide acetate (Somatuline Depot)
ENT cancer: Cetuximab (Erbitux)
Gastrointestinal tumours: imatinib mesylate (Glivec), sunitinib (Sutent), regrafenib (stivarga)
Giant cell tumors of the bone: denosumab (xgeva)
Kaposi sarcoma: Alitretinoin (Panretin)
Renal Cancer: Bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), pazopanib (Votrient), temsirolimus (Torisel), everolimus (Afinitor), axitinib (Inlyta)
Leukemia: Tretinoin (Vesanoid) imatinb mesylate (Gleevec), dasatinib (Sprycerl), nilotinib (Tasigna) nilotinib (Tasigna), Bosutinib (Bosulif), rituximab (Riruxan), alemtuzumab (Campath), ofatumumab (Arzerra), Rituximab (Mabtera ), obinutuzumab (Gazyva), ibrutinib (imbruvica) Indelalisib (Zydelig) blinatumomab (Blincyto)
Liver cancer: Sorafenib (Nexavar)
Lung Cancer: Bevacizumab (Avastin), crizotinib (Xalkori), erlotinib (Tarceva), gefitinib (Iressa), afatinib dimaletate (Gilotrif) ceritinib (LDK 378 / Zykadia), ramucirumab (Cyramza).
Malignant lymphoma : Ibritumomab tiuxetan (Zevalin), denileukin diftitox (ONTAK), brentuximab vedotin (Adcetris), rituximab (Rituxan), vorinostat (Zolinza), romidepsin (Istodax), bexarotene (Targretin), bortezomib (Velcade), pralatrexate (FOLOTYN) , lenaliomide (Revlimid), ibrutinib (Imbruvica) siltuximab (Sylvia), idelalisib (Zydelig), belinostat (Beleodaq)
Melanoma: Ipilimumab (Yervoy), vemurafenib (Zelboraf), trametinib (Mekinist), dabrafenib (Tafinlar) pembrolizumab (Keytruda) nivolumab (Opdivo)
Multiple Myeloma: Bortezomib (Velcade), carfilzomib (Kyprolis), lenaliomide (Revlimid), pomalidomide (Pomalyst)
Myeloproliferative / myelodysplastic chronic syndromes: Imatinib mesylate (Gleevec), ruxolitinib (jakafi)
Ovarian cancer epithelial / primary peritoneal cancer / tubal cancer: Bevacizumab (Avastin), olaparib (Lynparza)
Pancreatic Cancer: Erlotinib (Tarceva), everolimus (Afinitor), sunitinib (Sutent)
Prostate Cancer: cabazitaxel (Jevtana), enzalutamide (Xtandi), abiraterone acetate (Zytiga), radium 223 chloride (Xofigo)
Soft Tissue Sarcoma: Pazopanib (Votrient)
Systemic mastocytosis: Imatinib mesylate (Gleevec)
Thyroid Cancer: Cabozantinib (Cometriq), vandetanib (Caprelsa), sorafenib (Nexavar)