Targeted therapy
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (
Another form of targeted therapy involves the use of nanoengineered enzymes to bind to a tumor cell such that the body's natural cell degradation process can digest the cell, effectively eliminating it from the body.
Targeted cancer therapies are expected to be more effective than older forms of treatments and less harmful to normal cells. Many targeted therapies are examples of
The most successful targeted therapies are chemical entities that target or preferentially target a protein or enzyme that carries a mutation or other genetic alteration that is specific to cancer cells and not found in normal host tissue. One of the most successful molecular targeted therapeutics is
There are targeted therapies for lung cancer, colorectal cancer, head and neck cancer, breast cancer, multiple myeloma, lymphoma, prostate cancer, melanoma and other cancers.[1][3][4]
Biomarkers are usually required to aid the selection of patients who will likely respond to a given targeted therapy.[5]
Co-targeted therapy involves the use of one or more therapeutics aimed at multiple targets, for example PI3K and MEK, in an attempt to generate a synergistic response[4] and prevent the development of drug resistance.[6][7]
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.[8]
Some have challenged the use of the term, stating that drugs usually associated with the term are insufficiently selective.
Types
The main categories of targeted therapy are currently small molecules and monoclonal antibodies.
Small molecules
Many are
- Imatinib (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,[11] 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.
- Sorafenib (Nexavar)[12]
- Sunitinib (Sutent)
- Dasatinib (Sprycel)
- Lapatinib (Tykerb)
- Nilotinib (Tasigna)
- 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.[13]
- Janus kinase inhibitors, e.g. FDA approved tofacitinib
- ALK inhibitors, e.g. crizotinib
- Bcl-2 inhibitors (e.g. FDA approved venetoclax, obatoclax in clinical trials, navitoclax, and gossypol.[14]
- PARP inhibitors (e.g. FDA approved olaparib, rucaparib, niraparib and talazoparib)
- PI3K inhibitors (e.g. perifosinein a phase III trial)
- LHRH, Phase II results for ovarian cancer.[17]
- LGX818) used to treat metastatic melanomathat harbors BRAF V600E mutation
- MEK162) are used in experiments, often in combination with BRAF inhibitors to treat melanoma
- LEE011in clinical trials
- Hsp90 inhibitors, some in clinical trials
- Hedgehog pathway inhibitors (e.g. FDA approved vismodegib and sonidegib).
- cancer stem cellsin both laboratory-created and naturally occurring breast tumors in mice.
- clinical trials as a potential treatment for glioblastoma (GBM) and ovarian cancer. As of July 2017, four different trials of VAL-083 are registered.[20]
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).[21]
Serine/threonine kinase inhibitors (small molecules)
- Temsirolimus (Torisel)
- Everolimus (Afinitor)
- Vemurafenib (Zelboraf)
- Trametinib (Mekinist)
- Dabrafenib (Tafinlar)
Monoclonal antibodies
Several are in development and a few have been licensed by the FDA and the European Commission. Examples of licensed monoclonal antibodies include:
- non-small cell lung carcinoma and several other types of cancer.[23]
- Rituximab targets CD20 found on B cells. It is used in non Hodgkin lymphoma
- Her2/neu (also known as ErbB2) receptor expressed in some types of breast cancer
- Alemtuzumab
- Panitumumab also targets the EGFR. It is approved for the use in the treatment of metastatic colorectal 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.[28]
- Ipilimumab (Yervoy)
Many
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
References
- ^ PMID 34661151.
- ^ "Definition of targeted therapy – NCI Dictionary of Cancer Terms".
- ^ "Targeted Cancer Therapies". National Cancer Institute. 15 September 2021.
- ^ PMID 24055012.
- S2CID 205908189.
- PMID 29374181.
- PMID 25025901.
- 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". Proceedings of the National Academy of Sciences of the United States of America. 83 (23): 9129–9133.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.S2CID 26000048. - S2CID 1223977.
- S2CID 44821306.
- PMID 19159467.
- ISBN 978-1-63321-687-7.
- PMID 18068350.
- PMID 19079626.
- PMID 20923544.
- ^ "Apatinib". clinicaltrials.gov.
- ^ "Phase II study of AEZS-108 (AN-152), a targeted cytotoxic LHRH analog, in patients with LHRH receptor-positive platinum resistant ovarian cancer". 2010.
- .
- .
- ^ "VAL-083 Clinical Trials". ClinicalTrials.Gov. U.S. National Institutes of Health.
- ^ "Merck, Endocyte in Development Deal". dddmag.com. 25 April 2012.
- ^ "Keytruda". National Cancer Institute. 2011-02-02.
- ^ "Pembrolizumab Use in Cancer". National Cancer Institute. 2014-09-18.
- ^ "Therascreen KRAS RGQ PCR Kit – P110030“. Device Approvals and Clearances. U.S. Food and Drug Administration. 2012-07-06.
- ^ European medicines Agency (June 2014). “Erbitux® Summary of Product Characteristics (PDF).“ 2015-11-19.
- ^ “Cetuximab (Erbitux). About the Center of Drug Evaluation and Research." U.S. Food and Drug Administration. 2015-11-16.
- ^ "Merck KGaA: European Commission Approves Erbitux for First-Line Use in Head and Neck Cancer" 2015-11-16
- New York Times. Retrieved 2009-08-13.
External links
- Targeted Therapy Database (TTD) [1] from the Melanoma Molecular Map Project [2]
- 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)
- Targeting tumors with medicinal cannabis oil – publication list from Spain