Targeted therapy
From Wikipedia, the free encyclopedia
Targeted therapy or molecularly 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 all rapidly dividing cells (e.g. with traditional chemotherapy). Radiotherapy is not considered a 'targeted therapy' despite its often being aimed at the tumours.
Targeted cancer therapies are expected to be more effective than current treatments and less harmful to normal cells.
There are targeted therapies for breast cancer, multiple myeloma, lymphoma, prostate cancer, melanoma and other cancers.[2]
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 and reported from 1985.[3]
Some have challenged use of the term, stating that drugs usually associated with the term are insufficiently selective.[4] The phrase occasionally appears in scare quotes: "targeted therapy".[5]
Types
The main categories of targeted therapy are small molecules, small molecule drug conjugates and monoclonal antibodies.
Small molecules
Mechanism of imatinib
Many are tyrosine-kinase inhibitors.
- 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.
- Erlotinib (marketed as Tarceva). Erlotinib inhibits epidermal growth factor receptor,[6] 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.[7]
- Janus kinase inhibitors, e.g. FDA approved tofacitinib
- ALK inhibitors, e.g. crizotinib
- Bcl-2 inhibitors (e.g. obatoclax in clinical trials, ABT-263, and Gossypol.[8]
- PARP inhibitors (e.g. Iniparib, Olaparib in clinical trials)
- PI3K inhibitors (e.g. perifosine in a phase III trial)
- Apatinib is a selective VEGF Receptor 2 inhibitor which has shown encouraging anti-tumor activity in a broad range of malignancies in clinical trials.[9] Apatinib is currently in clinical development for metastatic gastric carcinoma, metastatic breast cancer and advanced hepatocellular carcinoma.[10]
- AN-152, (AEZS-108) doxorubicin linked to [D-Lys(6)]- LHRH, Phase II results for ovarian cancer.[11]
- Braf inhibitors (vemurafenib, dabrafenib, LGX818) used to treat metastatic melanoma that harbors BRAF V600E mutation
- MEK inhibitors (trametinib, MEK162) are used in experiments, often in combination with BRAF inhibitors to treat melanoma
- CDK inhibitors, e.g. PD-0332991, LEE011 in clinical trials
- Hsp90 inhibitors, some in clinical trials
- salinomycin has demonstrated potency in killing cancer stem cells in both laboratory-created and naturally occurring breast tumors in mice.
Small Molecule Drug Conjugates
- Vintafolide is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor. It is currently in clinical trials for platinum-resistant ovarian cancer (PROCEED trial) and a Phase 2b study(TARGET trial) in non-small-cell lung carcinoma (NSCLC).[12]
Monoclonal antibodies
Main article: Monoclonal antibody therapy
Several are in development and a few have been licenced by the FDA. Examples of licenced monoclonal antibodies include:
- Rituximab (marketed as MabThera or Rituxan) 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.[13]
Many Antibody-drug conjugates (ADCs) are being developed. See also ADEPT (Antibody-directed enzyme prodrug therapy).
Progress and future
In the U.S., the National Cancer Institute's Molecular Targets Development Program (MTDP) aims to identify and evaluate molecular targets that may be candidates for drug development.
See also
- History of cancer chemotherapy#Targeted therapy
- Targeted drug delivery
- Targeted molecular therapy for neuroblastoma
- Targeted therapy of lung cancer
- Treatment of lung cancer#Targeted therapy
References
- ↑ "Definition of targeted therapy - NCI Dictionary of Cancer Terms".
- ↑ NCI: Targeted Therapy tutorials
- ↑ 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.
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.
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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Li J, Zhao X, Chen L, et al. (2010). "Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies". BMC Cancer 10: 529. doi:10.1186/1471-2407-10-529. PMC 2984425. PMID 20923544.
- ↑ 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.dddmag.com/news/2012/04/merck-endocyte-development-deal}}
- ↑ Pollack, Andrew (2009-03-31). "F.D.A. Panel Supports Avastin to Treat Brain Tumor". New York Times. Retrieved 2009-08-13.
External links
- CancerDriver : a free and open database to find targeted therapies according to the patient's features.
- Targeted Therapy Database (TTD) from the Melanoma Molecular Map Project
- Targeted therapy Fact sheet from the U.S. National Cancer Institute
- Molecular Oncology: Receptor-Based Therapy Special issue of Journal of Clinical Oncology (April 10, 2005) dedicated to targeted therapies in cancer treatment
- Targeting Targeted Therapy New England Journal of Medicine (2004)
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