Targeted therapy
Encyclopedia
Targeted therapy is a type of medication
that blocks the growth of cancer cell
s by interfering with specific targeted molecules needed for carcinogenesis
and tumor
growth, rather than by simply interfering with rapidly dividing cells (e.g. with traditional chemotherapy
). Targeted cancer therapies may be more effective than current treatments and less harmful to normal cells.
The definitive experiments that showed that targeted therapy would reverse the malignant phenotype of tumor cells involved treating Her2/neu transformed cells with monoclonal antibodies in vitro and in vivo by Mark Greene’s laboratory.
Some have challenged use of the term, stating that drugs usually associated with the term are insufficiently selective. The phrase occasionally appears in scare quotes.
s and monoclonal antibodies.
Many Antibody-drug conjugate
s (ADCs) are being developed. See also ADEPT
(Antibody-directed enzyme prodrug therapy).
condition, methods for long-term treatment, with fewer side-effects, continue to be investigated.
In the U.S., the National Cancer Institute
's Molecular Targets Development Program (MTDP) to identify and evaluate molecular targets that may be candidates for drug development.
The next stage of targeted therapies will focus on finding which patients will respond to which targeted therapies. This is called the identification of "sub-populations", stratified medicine
or even personalized medicine
. The route to identify these sub-populations is through biomarkers and surrogate endpoint
s.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
that blocks the growth of cancer cell
Cancer cell
Cancer cells are cells that grow and divide at an unregulated, quickened pace. Although cancer cells can be quite common in a person they are only malignant when the other cells fail to recognize and/or destroy them. In the past a common belief was that cancer cells failed to be recognized and...
s by interfering with specific targeted molecules needed for carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
and tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
growth, rather than by simply interfering with rapidly dividing cells (e.g. with traditional chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
). Targeted cancer therapies may be more effective than current treatments and less harmful to normal cells.
The definitive experiments that showed that targeted therapy would reverse the malignant phenotype of tumor cells involved treating Her2/neu transformed cells with monoclonal antibodies in vitro and in vivo by Mark Greene’s laboratory.
Some have challenged use of the term, stating that drugs usually associated with the term are insufficiently selective. The phrase occasionally appears in scare quotes.
Types
The main categories of targeted therapy are small moleculeSmall molecule
In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...
s and monoclonal antibodies.
Small molecules
- Imatinib mesylateImatinibImatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
(Gleevec, also known as STI–571) is approved for chronic myelogenous leukemiaChronic myelogenous leukemiaChronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
, gastrointestinal stromal tumorGastrointestinal stromal tumorA gastrointestinal stromal tumor is one of the most common mesenchymal tumors of the gastrointestinal tract...
and some other types of cancer. Early clinical trials indicate that imatinib may be effective in treatment of dermatofibrosarcoma protuberansDermatofibrosarcoma protuberansDermatofibrosarcoma protuberans is a very rare tumor. It is a rare neoplasm of the dermis layer of the skin, and is classified as a sarcoma. There is only about 1 case per million per year. DFSP is a fibrosarcoma, more precisely a cutaneous soft tissue sarcoma...
. - GefitinibGefitinibGefitinib INN , trade name Iressa, is a drug used in the treatment of certain types of cancer, particularly those with mutated and overactive EGFR. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor in target cells...
(Iressa, also known as ZD1839), targets the epidermal growth factor receptorEpidermal growth factor receptorThe epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR) tyrosine kinaseTyrosine kinaseA tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
and is approved in the U.S. for non small cell lung cancerLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
. EGFR is also overexpressed in the cells of other solid tumors, such as lung and breast cancers. This leads to inappropriate activation of the apoptoticApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
RasRasRas is the name given to a family of related proteins found inside cells, including human cells. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells...
signal transductionSignal transductionSignal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
cascade, eventually leading to uncontrolled cell proliferation.Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphateAdenosine triphosphateAdenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited; and malignant cells are inhibited. - ErlotinibErlotinibErlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor . It is marketed in the United States by Genentech and OSI...
(marketed as Tarceva). Erlotinib inhibits epidermal growth factor receptorEpidermal growth factor receptorThe epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
, and works through a similar mechanism as gefitinib. Erlotinib has been shown to increase survival in metastatic non small cell lung cancerLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
when used as second line therapy. Because of this finding, erlotinib has replaced gefitinib in this setting. - BortezomibBortezomibBortezomib is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma...
(Velcade) is an apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
-inducing proteasome inhibitorProteasome inhibitorProteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Proteasome inhibitors are being studied in the treatment of cancer.-Examples:...
drug that causes cancer cells to undergo cell death by interfering with proteins. It is approved in the U.S. to treat multiple myelomaMultiple myelomaMultiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
that has not responded to other treatments. - The selective estrogen receptor modulatorSelective estrogen receptor modulatorSelective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
tamoxifenTamoxifenTamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
has been described as the foundation of targeted therapy. - Bcl-2 inhibitors (e.g. obatoclaxObatoclaxObatoclax is an experimental drug candidate for the treatment of various types of cancer. It was discovered by Gemin X, which was acquired by Cephalon. It is in Phase II clinical trials for the treatment of leukemia, lymphoma, myelofibrosis, and mastocytosis.-Mechanism of action:Obatoclax is an...
in clinical trials, ABT-263, and GossypolGossypolGossypol is a natural phenol derived from the cotton plant . Gossypol is a phenolic aldehyde that permeates cells and acts as an inhibitor for several dehydrogenase enzymes. It is a yellow pigment....
. - PARP inhibitorPARP inhibitorPARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase . They are developed for multiple indications; the most important is the treatment of cancer...
s (e.g. Iniparib, Olaparib in clinical trials) - Janus kinase inhibitorJanus kinase inhibitorJanus kinase inhibitor is a class of medicines that function by inhibiting the effect of one or more of the Janus kinase family of enzymes , interfering with the JAK-STAT signaling pathway....
s - PI3K inhibitors
- ApatinibApatinibApatinib, also known as YN968D1, is a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2...
is a selective VEGF Receptor 2 inhibitor which has shown encouraging anti-tumor activity in a broad range of malignancies in clinical trials. Apatinib is currently in clinical development for metastatic gastric carcinoma, metastatic breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and advanced hepatocellular carcinomaHepatocellular carcinomaHepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
. - AN-152, (AEZS-108) doxorubicinDoxorubicinDoxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
linked to [D-Lys(6)]- LHRH, Phase II results for ovarian cancer - salinomycinSalinomycinSalinomycin is an antibacterial and coccidiostat ionophore therapeutic drug.- Use in cancer :Salinomycin has been shown by Piyush Gupta et al. of the Massachusetts Institute of Technology and the Broad Institute to kill breast cancer stem cells at least 100 times more effectively than another...
has demonstrated potency in killing cancer stem cells in both laboratory-created and naturally occurring breast tumors in mice.
Monoclonal antibodies
Several are in development and a few have been licenced by the FDA. Examples of licenced monoclonal antibodies include:- RituximabRituximabRituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
(marketed as MabThera or Rituxan) targets CD20 found on B cells. It is used in non Hodgkin lymphomaLymphomaLymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage... - TrastuzumabTrastuzumabTrastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...
(Herceptin) targets the Her2/neuHER2/neuHER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
(also known as ErbB2) receptor expressed in some types of breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas... - CetuximabCetuximabCetuximab is a chimeric monoclonal antibody, an epidermal growth factor receptor inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer and head and neck cancer.- Distribution :Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers...
(marketed as Erbitux) targets the epidermal growth factor receptor. It is used in the treatment of colon cancer and non-small cell lung cancer. - BevacizumabBevacizumabBevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....
(marketed as Avastin) targets circulating VEGF ligand. It is approved for use in the treatment of colon cancer, breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, non-small cell lung cancer, and is investigational in the treatment of sarcomaSarcomaA sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
. Its use for the treatment of brain tumorBrain tumorA brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
s has been recommended.
Many Antibody-drug conjugate
Antibody-drug conjugate
Antibody-drug conjugates are a new type of targeted therapy, used for example for cancer. They consist of an antibody linked to a payload drug . Hence, they are a type of immunoconjugate and often an immunotoxin.The antibody causes the ADC to bind to the target cancer cells...
s (ADCs) are being developed. See also ADEPT
ADEPT
ADEPT is a strategy to overcome the problems of lack of tumor selectivity. An antibody designed/developed against a tumor antigen is linked to an enzyme and injected to the blood, resulting in selective binding of the enzyme in the tumor...
(Antibody-directed enzyme prodrug therapy).
Progress and future
Many oncologists believe that targeted therapies are the chemotherapy of the future. As solid tumor cancer continues to be viewed as a chronicChronic (medicine)
A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...
condition, methods for long-term treatment, with fewer side-effects, continue to be investigated.
In the U.S., the National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
's Molecular Targets Development Program (MTDP) to identify and evaluate molecular targets that may be candidates for drug development.
The next stage of targeted therapies will focus on finding which patients will respond to which targeted therapies. This is called the identification of "sub-populations", stratified medicine
Stratified medicine
Stratified medicine is the management of a group of patients with shared biological characteristics by using molecular diagnostic testing to select the best therapy in order to achieve the best possible medicinal outcome for that group....
or even personalized medicine
Personalized medicine
Personalized medicine is a medical model emphasizing in general the customization of healthcare, with all decisions and practices being tailored to individual patients in whatever ways possible...
. The route to identify these sub-populations is through biomarkers and surrogate endpoint
Surrogate endpoint
In clinical trials, a surrogate endpoint is a measure of effect of a certain treatment that may correlate with a real clinical endpoint but doesn't necessarily have a guaranteed relationship...
s.
External links
- Targeted Therapy Database (TTD) http://www.mmmp.org/MMMP/import.mmmp?page=targetedtherapydatabase.mmmp from the Melanoma Molecular Map Project http://www.mmmp.org/MMMP/welcome.mmmp
- Fact sheet from the U.S. National Cancer InstituteNational Cancer InstituteThe National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
- Molecular Oncology: Receptor-Based Therapy Special issue of Journal of Clinical OncologyJournal of Clinical OncologyThe Journal of Clinical Oncology is a medical journal published 3 times a month by the American Society of Clinical Oncology , with a 2009 impact factor of 17.793...
(April 10, 2005) dedicated to targeted therapies in cancer treatment - Targeting Targeted Therapy New England Journal of Medicine (2004)