Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells (eg. with traditional chemotherapy). Targeted cancer therapies may be more effective than current treatments and less harmful to normal cells.
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. 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.
Types
The main categories of targeted therapy are small molecules and monoclonal antibodies.
Small molecules
- Imatinib mesylate (Gleevec, also known as STI–571) is approved for chronic myelogenous leukemia, gastrointestinal stromal tumor and some other types of cancer. Early clinical trials indicate that imatinib may be effective in treatment of dermatofibrosarcoma protuberans.
- Gefitinib (Iressa, also known as ZD1839), targets the epidermal growth factor receptor (EGFR) tyrosine kinase and is approved in the U.S. for non small cell lung cancer. EGFR is also overexpressed in the cells of other solid tumors, such as lung and breast cancers. This leads to inappropriate activation of the apoptotic Ras signal transduction cascade, eventually leading to uncontrolled cell proliferation.Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (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.
- Erlotinib (marketed as Tarceva). Erlotinib inhibits epidermal growth factor receptor, and works through a similar mechanism as gefitinib. Erlotinib has been shown to increase survival in metastatic non small cell lung cancer when used as second line therapy. Because of this finding, erlotinib has replaced gefitinib in this setting.
- Bortezomib (Velcade) is an apoptosis-inducing drug that causes cancer cells to undergo cell death by interfering with proteins. It is approved in the U.S. to treat multiple myeloma that has not responded to other treatments.
- Newer BCL-2 antagonists, such as Obatoclax, ABT-263, and Gossypol.
- The selective estrogen receptor modulator tamoxifen has been described as the foundation of targeted therapy.
Monoclonal antibodies
Main article: Monoclonal antibody therapySeveral are in development and a few have been licenced by the FDA. Examples of licenced monoclonal antibodies include:
- Rituximab targets CD20 found on B cells. It is used in non Hodgkin lymphoma
- Trastuzumab (Herceptin) targets the Her2/neu (also known as ErbB2) receptor expressed in some types of breast cancer
- Cetuximab (marketed as Erbitux) targets the epidermal growth factor receptor. It is used in the treatment of colon cancer and non-small cell lung cancer.
- Bevacizumab (marketed as Avastin) targets circulating VEGF ligand. It is approved for use in the treatment of colon cancer, breast cancer, non-small cell lung cancer, and is investigational in the treatment of sarcoma. Its use for the treatment of brain tumors has been recommended.
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 chronic condition, methods for long-term treatment, with less 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". The route to identify these sub-populations is through biomarkers and surrogate endpoints.
One agent which seems to be promising is cannabidiol, a non-toxic substance found in cannabis which has been found to reduce growth and invasiveness of cancer cells in vitro.
Another promising chemical is salinomycin, which has demonstrated potency in killing cancer stem cells in both laboratory-created and naturally occurring breast tumors in mice.
References
- ^ "Definition of targeted therapy - NCI Dictionary of Cancer Terms" . http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=270742 . Retrieved 2009-01-25 .
- ^ Zhukov NV, Tjulandin SA (May 2008). "Targeted therapy in the treatment of solid tumors: practice contradicts theory". Biochemistry Mosc. 73 (5): 605–18. PMID 18605984 . http://protein.bio.msu.ru/biokhimiya/contents/v73/full/73050751.html .
- ^ Markman M (2008). "The promise and perils of 'targeted therapy' of advanced ovarian cancer". Oncology 74 (1-2): 1–6. doi: 10.1159/000138349 . PMID 18536523 . http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000138349 .
- ^ "Activated neu oncogene sequences in primary tumors of the peripheral nervous system induced in rats by transplacental exposure to ethylnitrosourea" . http://www.ncbi.nlm.nih.gov/pubmed/3476947?ordinalpos=12&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum&log$=freepmc . "Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen" . http://www.ncbi.nlm.nih.gov/pubmed/3466178?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum . "Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies" . http://www.ncbi.nlm.nih.gov/pubmed/2860972?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum .
- ^ Katzel JA, Fanucchi MP, Li Z (January 2009). "Recent advances of novel targeted therapy in non-small cell lung cancer". J Hematol Oncol 2 (1): 2. doi: 10.1186/1756-8722-2-2 . PMID 19159467 . http://www.jhoonli
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