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Targeted therapy

Targeted therapy or molecular-targeted ("molecular-targeted") therapy (eng.target "target, target ") is one of the significant areas of drug treatment (pharmacotherapy) of cancer ; others are hormone therapy and chemotherapy . As a type of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with the mechanism of action of specific target (target) molecules necessary for carcinogenesis and tumor growth, [1] and not just preventing the multiplication of all rapidly dividing cells (as, for example, traditional chemotherapy). Since most drugs for targeted therapy are biopharmaceuticals , the term biological therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy (and, therefore, differs from chemotherapy, i.e. cytotoxic therapy). However, these methods can be used in combination with each other, when antibody-based drug complexes combine biological and cytotoxic mechanisms in a single targeted drug.

Targeted cancer therapy is expected to be more effective than previous treatments and less harmful to normal cells. Many targeted therapies are examples of immunotherapy (as they use immune mechanisms for therapeutic purposes), developed in the field of oncoimmunology . Thus, being immunomodulators , they are one of the types of biological response modifiers.

The most successful targeted therapies use chemical substances that target or predominantly target a protein or enzyme that carries a mutation or other genetic changes that are specific to cancer cells and are not present in normal host tissue. One of the most successful molecular targeted drugs is Gleevec, which is a kinase inhibitor with exceptional affinity for the BCR-ABL fusion protein, which is an important factor in oncogenesis in chronic myelogenous leukemia. Despite a number of other indications, Gleevec is most effective against BCR-ABL. Other examples of molecular targeting drugs that suppress mutated oncogenes include PLX27892 which targets mutant B-Raf in melanoma.

There are targeted drugs for the treatment of breast cancer, multiple myeloma, lymphoma, prostate cancer , melanoma and other cancers [2] .

Decisive experiments, which showed that molecular targeted therapy can reverse the development of a malignant phenotype of tumor cells, were carried out in the treatment of HER2 / NEU transformed cells with monoclonal antibodies in vitro (in vitro) and in vivo (in vivo) in Mark Green's laboratory, and their conducting has been covered since 1985 [3] .

Some have disputed the use of the term, saying that such drugs are usually not selective enough [4] . Targeted drugs could also be considered “ chemotherapy ” or “non-cytotoxic chemotherapy,” as in the broad sense “chemotherapy” means “chemical treatment” in general. However, in the medical use of the term “chemotherapy”, the term “chemotherapy” is currently mainly used only for “traditional” chemotherapy.

Content

Types of targeted drugs

The main categories of targeted drugs are currently based on two types of substances: small molecules (low molecular weight biologically active substances) and monoclonal antibodies

Tyrosine kinase inhibitors (small molecules)

 
The mechanism of action of imatinib

Many are tyrosine kinase inhibitors.

  • Imatinib mesylate (Glivec, also known as STI-571) is intended for the treatment of chronic myeloid leukemia of a gastrointestinal stromal tumor and some other cancers. Early clinical trials show that imatinib may be effective in treating dermatofibrosarcoma protuberans.
  • Gefitinib (Iressa, also known as ZD1839), targets the epidermal growth factor receptor (EGFR) tyrosine kinase and is approved in the United States for non-small cell lung cancer.
  • Erlotinib (trade name Tarceva). Erlotinib inhibits the epidermal growth factor receptor , [5] and has a similar mechanism of action with gefitinib. Erlotinib showed an increase in the survival of patients with metastatic non-small cell lung cancer when used as second-line therapy. Because of this fact, erlotinib has replaced gefitinib for this disease.
  • Sorafenib (Nexavar) [6]
  • Sunitinib (Sutent)
  • Dasatinib (Sprycel)
  • Lapatinib (Tykerb)
  • Nilotinib (Tasigna)
  • Bortezomib (Velcade) is a proteasome inhibitor, a drug that causes apoptosis ; under the influence of its cancer cells undergo cell death, since it disrupts the synthesis of their proteins. It is approved in the United States for the treatment of multiple myeloma, which has not responded to other treatments.
  • The selective estrogen receptor modulator tamoxifen has been described as the basis for targeted therapy. [7]
  • Janus kinase inhibitors, e.g. FDA-approved tofacitinib
  • ALK inhibitor, eg, chrysotinib [8]
  • Bcl-2 inhibitors (eg, obatoclax in clinical trials, navitoclax and gossypol . [9]
  • PARP inhibitors (e.g., iniparib, olaparib in clinical trials)
  • PI3K inhibitor (e.g., peripheral phase III clinical trials)
  • Apatinib is a selective inhibitor of VEGF receptor 2, which shows promising antitumor activity in a wide range of malignant neoplasms in clinical trials. [10] Apatinib is currently in clinical development for the treatment of metastatic gastric cancer, metastatic breast cancer, and advanced hepatic cancer . [eleven]
  • AN-152 (AEZS-108, doxorubicin ) binding to [D-Lys (6)] -. LHRH, Phase II clinical trial results for ovarian cancer [12]
  • BRAF inhibitors (vemurafenib [13] , dabrafenib [14] , LGX818) are used to treat metastatic melanoma that develops with the BRAF V600E mutation
  • MEK inhibitors (mitogen-activated protein kinase kinase kinases) (trametinib [15] , MEK162) ( MEK inhibitors ) are used in experiments, often in combination with BRAF inhibitors, to treat melanoma
  • Cyclin-dependent kinase ( CDK) inhibitors , e.g. PD-0332991, LEE011 - in clinical trials
  • Hsp90 inhibitors ( heat shock protein 90 inhibitors ), some in clinical trials
  • Salinomycin [16] [17] has been shown to be effective in the defeat of cancer stem cells in laboratory-induced and naturally developing breast tumors in mice.

Complex preparations of small molecules

  • Vintafolid [18] is a complex drug of small molecules, consisting of small molecules aimed at the folic acid receptor. He is currently in clinical trials for platinum drug-resistant ovarian cancer (PROCEED trials) and phase 2b trials (TARGET trials) against non-small cell lung cancer (NSCLC) [19] .

Serine / Threonine Kinase Inhibitors (Small Molecules)

  • Temsirolimus (Torisel)
  • Everolimus (Athenitor)
  • Vemurafenib (Zelboraf)
  • Trametinib (Meckinist)
  • Dabrafenib (Tafinlar)

Monoclonal Antibodies

Several are under development, and several have been licensed by the FDA. Examples of licensed monoclonal antibodies include:

  • Rituximab (trade names Mabtera or Rituxan) target CD20 in B cells . It is used for non-Hodgkin lymphomas .
  • Trastuzumab (Herceptin [20] ) targets the HER2 / Neu receptor (also known as ErbB2), expressed in some types of breast cancer
  • Alemtuzumab
  • Cetuximab (trade name Erbitux) and Panitumumab target the epidermal growth factor receptor (EGFR). They are used in the treatment of colon cancer and non-small cell lung cancer.
  • Bevacizumab (trade name Avastin ) targets a circulating VEGF ligand. It is approved for use in the treatment of colon cancer, breast cancer, non-small cell lung cancer, and is being investigated for the treatment of sarcoma. Recommended use for the treatment of brain tumors [21]
  • Ipilimumab

Currently, many complex preparations of the "antibody-drug" with (ADC) are being developed. See also ADEPT (antibody-directed enzymatic prodrugs ).

Progress and Future

The US National Cancer Institute’s Molecular Targeted Drug Development Program has been launched in the United States to identify and evaluate molecular targets that might be candidates for drug development.

Links

  • CancerDriver: A free and open database for finding targeted drugs according to your patient’s needs.
  • Targeted Therapy Database [1] Project for Molecular Mapping of Melanoma [2]
  • Targeted therapy Fact sheet from the US 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)

See also

  • History of Cancer Chemotherapy
  • Targeted Drug Delivery
  • Targeted molecular therapy of neuroblastoma
  • Targeted lung cancer therapy
  • Lung cancer treatment
  • Specific covalent inhibitors

Sources

  1. ↑ Definition of targeted therapy - NCI Dictionary of Cancer Terms (neopr.) .
  2. ↑ NCI: Targeted Therapy tutorials
  3. ↑ Perantoni AO, Rice JM, Reed CD, Watatani M., Wenk ML Activated neu oncogene sequences in primary tumors of the peripheral nervous system induced in rats by transplacental exposure to ethylnitrosourea (Eng.) // Proceedings of the National Academy of Sciences of the United States of America : journal. - 1987 .-- September ( vol. 84 , no. 17 ). - P. 6317-6321 . - DOI : 10.1073 / pnas.84.17.6317 . - PMID 3476947 .
    Drebin JA, Link VC, Weinberg RA, Greene MI Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen (Eng.) // Proceedings of the National Academy of Sciences of the United States of America : journal. - 1986 - December ( vol. 83 , no. 23 ). - P. 9129-9133 . - DOI : 10.1073 / pnas.83.23.9129 . - PMID 3466178 .
    Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies (Eng.) // Cell : journal. - Cell Press 1985 .-- July ( vol. 41 , no. 3 ). - P. 697–706 . - DOI : 10.1016 / S0092-8674 (85) 80050-7 . - PMID 2860972 .
  4. ↑ Zhukov NV, Tjulandin SA Targeted therapy in the treatment of solid tumors: practice contradicts theory (Eng.) // Biochemistry Mosc. : journal. - 2008 .-- May ( vol. 73 , no. 5 ). - P. 605-618 . - DOI : 10.1134 / S000629790805012X . - PMID 18605984 .
  5. ↑ Katzel JA, Fanucchi MP, Li Z. Recent advances of novel targeted therapy in non-small cell lung cancer (Eng.) // J Hematol Oncol: journal. - 2009 .-- January ( vol. 2 , no. 1 ). - P. 2 . - DOI : 10.1186 / 1756-8722-2-2 . - PMID 19159467 .
  6. ↑ Lacroix, Marc. Targeted Therapies in Cancer . - Hauppauge, NY: Nova Sciences Publishers, 2014 .-- ISBN 978-1-63321-687-7 . Archived June 26, 2015 on Wayback Machine
  7. ↑ Jordan VC Tamoxifen: catalyst for the change to targeted therapy (English) // Eur. J. Cancer : journal. - 2008 .-- January ( vol. 44 , no. 1 ). - P. 30-38 . - DOI : 10.1016 / j.ejca.2007.11.11.002 . - PMID 18068350 .
  8. ↑ KRYZOTINIB | Active substances (neopr.) . www.vidal.ru. Date of treatment January 21, 2016.
  9. ↑ Warr MR, Shore GC Small-molecule Bcl-2 antagonists as targeted therapy in oncology (Eng.) // Curr Oncol : journal. - 2008 .-- December ( vol. 15 , no. 6 ). - P. 256—261 . - PMID 19079626 .
  10. ↑ Li J., Zhao X., Chen L., etal. Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies (English) // BMC Cancer : journal. - 2010 .-- Vol. 10 . - P. 529 . - DOI : 10.1186 / 1471-2407-10-529 . - PMID 20923544 .
  11. ↑ Search of: apatinib - List Results - ClinicalTrials.gov
  12. ↑ Phase II study of AEZS-108 (AN-152), a targeted cytotoxic LHRH analog, in patients with LHRH receptor-positive platinum resistant ovarian cancer. (unspecified) (2010).
  13. ↑ Zelboraf (Zelboraf, vemurafenib) - medicine, description, instructions, reviews, price, where to buy Zelboraf | Roche (neopr.) . www.roche.ru. Date of treatment January 21, 2016.
  14. ↑ Dabrafenib (Tafinalar) and Trametinib (Mekinist) are two new drugs approved by the FDA for the treatment of patients with melanoma (neopr.) . www.rosoncoweb.ru. Date of treatment January 21, 2016.
  15. ↑ Melanoma Unit, Ltd. Trametinib (Mekinist) (Russian) . assuta.melanomaunit.ru. Date of treatment January 21, 2016.
  16. ↑ treatment of oncological diseases, salinomycin antibiotic, autoantibodies, enzyme immunoassay systems, malignant cells :: Business Journal :: RBC Newspaper (Neopr.) (Link not available) . www.rbcdaily.ru. Date of treatment January 21, 2016. Archived January 26, 2016.
  17. ↑ alexander. Antitumor activity of the ionophore antibiotic salinomycin: target - tumor stem cells - Publishing House RUSSIAN DOCTOR (neopr.) (Link not available) . www.rusvrach.ru. Date of treatment January 21, 2016. Archived January 29, 2016.
  18. ↑ Vintafolid »Clinical Pharmacy. Magazine (unopened) . clinical-pharmacy.ru. Date of treatment January 21, 2016.
  19. ↑ Merck, Endocyte in Development Deal
  20. ↑ Roche in Russia - Instruction (Herceptin) (neopr.) . www.roche.ru. Date of treatment January 21, 2016.
  21. ↑ Pollack, Andrew . FDA Panel Supports Avastin to Treat Brain Tumor , New York Times (March 31, 2009). Date of treatment August 13, 2009.


Source - https://ru.wikipedia.org/w/index.php?title= Targeted therapy&oldid = 101025965


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