Patients and their diseases are profiled in order to identify the most effective treatment for their specific case.
Targeted therapy ormolecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) forcancer,[1] others beinghormonal therapy andcytotoxicchemotherapy. As a form ofmolecular medicine, targeted therapy blocks the growth ofcancer cells by interfering with specific targetedmolecules needed forcarcinogenesis andtumor growth,[2] rather than by simply interfering with allrapidly dividing cells (e.g. with traditionalchemotherapy). Because most agents for targeted therapy arebiopharmaceuticals, the termbiologic therapy is sometimes synonymous withtargeted therapy when used in the context of cancer therapy (and thus distinguished from chemotherapy, that is, cytotoxic therapy). However, the modalities can be combined;antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.
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 ofimmunotherapy (using immune mechanisms for therapeutic goals) developed by the field ofcancer immunology. Thus, asimmunomodulators, they are one type ofbiological response modifiers.
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.[3] One of the most successful molecular targeted therapeutics isimatinib, marketed as Gleevec, which is a kinase inhibitor with exceptional affinity for the oncofusion proteinBCR-Abl which is a strong driver of tumorigenesis inchronic myelogenous leukemia. Although employed in other indications, imatinib is most effective targeting BCR-Abl. Other examples of molecular targeted therapeutics targeting mutated oncogenes, include PLX27892 which targets mutant B-raf in melanoma.
Biomarkers are usually required to aid the selection of patients who will likely respond to a given targeted therapy.[6]
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[5] and prevent the development of drug resistance.[7][8]
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.[9]
Some have challenged the use of the term, stating that drugs usually associated with the term are insufficiently selective.[10] The phrase occasionally appears inscare quotes: "targeted therapy".[11] Targeted therapies may also be described as "chemotherapy" or "non-cytotoxic chemotherapy", as "chemotherapy" strictly means only "treatment by chemicals". But in typical medical and general usage "chemotherapy" is now mostly used specifically for "traditional" cytotoxic chemotherapy.
Erlotinib (marketed as Tarceva). Erlotinib inhibitsepidermal growth factor receptor,[12] and works through a similar mechanism as gefitinib. Erlotinib has been shown to increase survival in metastatic non small celllung cancer when used as second line therapy. Because of this finding, erlotinib has replaced gefitinib in this setting.
Bortezomib (Velcade) is anapoptosis-inducingproteasome inhibitor drug that causes cancer cells to undergo cell death by interfering with proteins. It is approved in the U.S. to treatmultiple myeloma that has not responded to other treatments.
Salinomycin has demonstrated potency in killingcancer stem cells in both laboratory-created and naturally occurring breast tumors in mice.
VAL-083 (dianhydrogalactitol), a “first-in-class” DNA-targeting agent with a unique bi-functional DNA cross-linking mechanism.[19][20]NCI-sponsored clinical trials have demonstrated clinical activity against a number of different cancers includingglioblastoma,ovarian cancer, andlung cancer. VAL-083 is currently undergoing Phase 2 and Phase 3clinical trials as a potential treatment forglioblastoma (GBM) and ovarian cancer. As of July 2017, four different trials of VAL-083 are registered.[21]
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).[22]
In the U.S., theNational Cancer Institute'sMolecular Targets Development Program (MTDP) aims to identify and evaluate molecular targets that may be candidates for drug development. A systematic review published in Cochrane database found that targeted therapies significantly improve progression-free survival by 35 to 40% in metastatic or relapsed cancer. While the research points to promising clinical outcomes, there is still limited evidence on the long-term effects of targeted therapies in terms of overall survival, quality of life, and severe adverse events.[30]
^abHeavey S, O'Byrne KJ, Gately K (April 2014). "Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC".Cancer Treatment Reviews.40 (3):445–456.doi:10.1016/j.ctrv.2013.08.006.PMID24055012.
^Syn NL, Yong WP, Goh BC, Lee SC (August 2016). "Evolving landscape of tumor molecular profiling for personalized cancer therapy: a comprehensive review".Expert Opinion on Drug Metabolism & Toxicology.12 (8):911–922.doi:10.1080/17425255.2016.1196187.PMID27249175.S2CID205908189.
^Zhukov NV, Tjulandin SA (May 2008). "Targeted therapy in the treatment of solid tumors: practice contradicts theory".Biochemistry. Biokhimiia.73 (5):605–618.doi:10.1134/S000629790805012X.PMID18605984.S2CID1223977.
^Steino A, He G, Bacha JA, Brown DM, Siddik Z (July 2017). "DNA damage response to dianhydrogalactitol (VAL-083) in p53-deficient non-small cell lung cancer cells".Cancer Research.77 (13 Supplement): 1429.doi:10.1158/1538-7445.AM2017-1429.
