Targeted therapy
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,[1] 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.[2]
Some have challenged use of the term, stating that drugs usually associated with the term are insufficiently selective.[3] The phrase occasionally appears in scare quotes.[4]
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,[5] 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 proteasome inhibitor 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.
- The selective estrogen receptor modulator tamoxifen has been described as the foundation of targeted therapy.[6]
- Bcl-2 inhibitors (e.g. obatoclax in clinical trials, ABT-263, and Gossypol.[7]
- PARP inhibitors (e.g. Iniparib, Olaparib in clinical trials)
- Janus kinase inhibitors
- PI3K inhibitors
- Apatinib is a selective VEGF Receptor 2 inhibitor which has shown encouraging anti-tumor activity in a broad range of malignancies in clinical trials.[8] Apatinib is currently in clinical development for metastatic gastric carcinoma, metastatic breast cancer and advanced hepatocellular carcinoma.[9]
- AN-152, (AEZS-108) doxorubicin linked to [D-Lys(6)]- LHRH, Phase II results for ovarian cancer[10]
- salinomycin has demonstrated potency in killing cancer stem cells in both laboratory-created and naturally occurring breast tumors in mice.[11][12]
Monoclonal antibodies
Several are in development and a few have been licenced by the FDA. Examples of licenced monoclonal antibodies include:
Many Antibody-drug conjugates (ADCs) are being developed. See also ADEPT (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 chronic 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 endpoints.
References
- ^ "Definition of targeted therapy - NCI Dictionary of Cancer Terms". http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=270742. Retrieved 2009-01-25.
- ^ Perantoni AO, Rice JM, Reed CD, Watatani M, Wenk ML (September 1987). "Activated neu oncogene sequences in primary tumors of the peripheral nervous system induced in rats by transplacental exposure to ethylnitrosourea". Proc. Natl. Acad. Sci. U.S.A. 84 (17): 6317–6321. doi:10.1073/pnas.84.17.6317. PMC 299062. PMID 3476947. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=299062.
Drebin JA, Link VC, Weinberg RA, Greene MI (December 1986). "Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen". Proc. Natl. Acad. Sci. U.S.A. 83 (23): 9129–9133. doi:10.1073/pnas.83.23.9129. PMC 387088. PMID 3466178. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=387088.
Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI (July 1985). "Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies". Cell 41 (3): 697–706. doi:10.1016/S0092-8674(85)80050-7. PMID 2860972.
- ^ Zhukov NV, Tjulandin SA (May 2008). "Targeted therapy in the treatment of solid tumors: practice contradicts theory". Biochemistry Mosc. 73 (5): 605–618. doi:10.1134/S000629790805012X. 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.
- ^ 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. PMC 2637898. PMID 19159467. http://www.jhoonline.org/content/2/1/2.
- ^ Jordan VC (January 2008). "Tamoxifen: catalyst for the change to targeted therapy". Eur. J. Cancer 44 (1): 30–38. doi:10.1016/j.ejca.2007.11.002. PMC 2566958. PMID 18068350. http://linkinghub.elsevier.com/retrieve/pii/S0959-8049(07)00861-1.
- ^ Warr MR, Shore GC (December 2008). "Small-molecule Bcl-2 antagonists as targeted therapy in oncology". Curr Oncol 15 (6): 256–61. PMC 2601021. PMID 19079626. http://www.current-oncology.com/index.php/oncology/article/view/392/306;.
- ^ http://www.biomedcentral.com/1471-2407/10/529
- ^ http://clinicaltrials.gov/ct2/results?term=apatinib
- ^ "Phase II study of AEZS-108 (AN-152), a targeted cytotoxic LHRH analog, in patients with LHRH receptor-positive platinum resistant ovarian cancer.". 2010. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=50099.
- ^ "New method takes aim at aggressive cancer cells". Broad Communications (Broad Institute). 2009-08-13. http://www.broadinstitute.org/news/1305. Retrieved 2009-08-13.
- ^ Gupta, P. et al. (2009-08-13). "Identification of selective inhibitors of cancer stem cells by high-throughput screening". Cell 138 (4): 645–659. doi:10.1016/j.cell.2009.06.034. PMID 19682730. http://www.cell.com/abstract/S0092-8674%2809%2900781-8. Retrieved 2009-08-13.
- ^ Pollack, Andrew (2009-03-31). "F.D.A. Panel Supports Avastin to Treat Brain Tumor". New York Times. http://www.nytimes.com/2009/04/01/business/01avastin.html. Retrieved 2009-08-13.
External links
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ErbB: HER1/EGFR (Erlotinib, Gefitinib, Vandetanib) • HER1/EGFR and HER2/neu (Afatinib, Lapatinib, Neratinib)
RTK class III: C-kit and PDGFR (Axitinib, Pazopanib, Sunitinib, Sorafenib, Toceranib) • FLT3 (Lestaurtinib)
VEGFR ( Axitinib, Cediranib, Pazopanib, Regorafenib, Semaxanib, Sorafenib, Sunitinib, Toceranib, Vandetanib)
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