Targeted therapy

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Patients and their diseases are profiled in order to identify the most effective treatment for their specific case. Targeted Therapy.svg
Patients and their diseases are profiled in order to identify the most effective treatment for their specific case.

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, [1] others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, [2] rather than by simply interfering with all rapidly dividing cells (e.g. with traditional chemotherapy). Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted 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.

Contents

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 immunotherapy (using immune mechanisms for therapeutic goals) developed by the field of cancer immunology. Thus, as immunomodulators, they are one type of biological 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. One of the most successful molecular targeted therapeutics is imatinib, marketed as Gleevec, which is a kinase inhibitor with exceptional affinity for the oncofusion protein BCR-Abl which is a strong driver of tumorigenesis in chronic 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.

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. [9] The phrase occasionally appears in scare quotes: "targeted therapy". [10] 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.

Types

The main categories of targeted therapy are currently small molecules and monoclonal antibodies.

Small molecules

Mechanism of imatinib Mechanism imatinib.svg
Mechanism of imatinib

Many are tyrosine-kinase inhibitors.

Small molecule drug conjugates

Serine/threonine kinase inhibitors (small molecules)

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:

Many antibody-drug conjugates (ADCs) are being developed. See also antibody-directed enzyme prodrug therapy (ADEPT).

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

Related Research Articles

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

<span class="mw-page-title-main">Gefitinib</span> Drug used in fighting breast, lung, and other cancers

Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspeciality of oncology.

<span class="mw-page-title-main">Erlotinib</span> EGFR inhibitor for treatment of non-small-cell lung cancer

Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.

<span class="mw-page-title-main">Non-small-cell lung carcinoma</span> Any type of epithelial lung cancer other than small-cell lung carcinoma

Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small-cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both preoperatively and postoperatively.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

<span class="mw-page-title-main">Tremelimumab</span>

Tremelimumab is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker. Previously in development by Pfizer, it is now in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca. It has been undergoing human trials for the treatment of various cancers but has not attained approval for any.

Triple-negative breast cancer (TNBC) is any breast cancer that lacks or show low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.

<span class="mw-page-title-main">Bi-specific T-cell engager</span>

Bi-specific T-cell engagers (BiTEs) are a class of artificial bispecific monoclonal antibodies that are investigated for the use as anti-cancer drugs. They direct a host's immune system, more specifically the T cells' cytotoxic activity, against cancer cells. BiTE is a registered trademark of Micromet AG.

<span class="mw-page-title-main">Afatinib</span> Chemical compound

Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.

Tigatuzumab (CS-1008) is a monoclonal antibody for the treatment of cancer. As of October 2009, a clinical trial for the treatment of pancreatic cancer, Phase II trials for colorectal cancer, non-small cell lung cancer, and ovarian cancer have been completed.

A CDK inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. Several compounds are in clinical trials.

Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care, alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.

<span class="mw-page-title-main">ALK inhibitor</span>

ALK inhibitors are anti-cancer drugs that act on tumours with variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK translocation. They fall under the category of tyrosine kinase inhibitors, which work by inhibiting proteins involved in the abnormal growth of tumour cells. All the current approved ALK inhibitors function by binding to the ATP pocket of the abnormal ALK protein, blocking its access to energy and deactivating it. A majority of ALK-rearranged NSCLC harbour the EML4-ALK fusion, although as of 2020, over 92 fusion partners have been discovered in ALK+ NSCLC. For each fusion partner, there can be several fusion variants depending on the position the two genes were fused at, and this may have implications on the response of the tumour and prognosis of the patient.

<span class="mw-page-title-main">Nivolumab</span> Cancer drug

Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction (GEJ) cancer. It is used by slow injection into a vein.

<span class="mw-page-title-main">Cancer biomarker</span> Substance or process that is indicative of the presence of cancer in the body

A cancer biomarker refers to a substance or process that is indicative of the presence of cancer in the body. A biomarker may be a molecule secreted by a tumor or a specific response of the body to the presence of cancer. Genetic, epigenetic, proteomic, glycomic, and imaging biomarkers can be used for cancer diagnosis, prognosis, and epidemiology. Ideally, such biomarkers can be assayed in non-invasively collected biofluids like blood or serum.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is given by slow injection into a vein.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), small cell lung cancer (SCLC), and hepatocellular carcinoma (HCC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

Metronomic therapy is a new type of chemotherapy in which anti-cancer drugs are administered in a lower dose than the maximum tolerated dose repetitively over a long period to treat cancers with fewer side effects. Metronomic therapy is shown to affect both tumor microenvironment and tumor cells to achieve its therapeutic effects. Metronomic therapy is also cost-effective as a lower dose is used compared to conventional chemotherapy. The use of metronomic therapy has been extensively investigated and can be advantageous in selected group of patients. Yet, more clinical trials are necessary to generalize the method.

Roy S. Herbst is an American oncologist who is the Ensign Professor of Medicine, Professor of Pharmacology, Chief of Medical Oncology, and Associate Director for Translational Research at Yale Cancer Center and Yale School of Medicine in New Haven, Connecticut.

References

  1. 1 2 Cordo' V, van der Zwet JC, Canté-Barrett K, Pieters R, Meijerink JP (January 2021). "T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies". Blood Cancer Discovery. 2 (1): 19–31. doi: 10.1158/2643-3230.BCD-20-0093 . PMC   8447273 . PMID   34661151.
  2. ↑ "Definition of targeted therapy – NCI Dictionary of Cancer Terms".
  3. ↑ "Targeted Cancer Therapies". National Cancer Institute. 15 September 2021.
  4. 1 2 Heavey 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. PMID   24055012.
  5. ↑ 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. PMID   27249175. S2CID   205908189.
  6. ↑ Heavey S, Dowling P, Moore G, Barr MP, Kelly N, Maher SG, et al. (January 2018). "Development and characterisation of a panel of phosphatidylinositide 3-kinase - mammalian target of rapamycin inhibitor resistant lung cancer cell lines". Scientific Reports. 8 (1): 1652. Bibcode:2018NatSR...8.1652H. doi:10.1038/s41598-018-19688-1. PMC   5786033 . PMID   29374181.
  7. ↑ Heavey S, Godwin P, Baird AM, Barr MP, Umezawa K, Cuffe S, et al. (October 2014). "Strategic targeting of the PI3K-NFκB axis in cisplatin-resistant NSCLC". Cancer Biology & Therapy. 15 (10): 1367–1377. doi:10.4161/cbt.29841. PMC   4130730 . PMID   25025901.
  8. ↑ 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". Proceedings of the National Academy of Sciences of the United States of America. 84 (17): 6317–6321. Bibcode:1987PNAS...84.6317P. 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". Proceedings of the National Academy of Sciences of the United States of America. 83 (23): 9129–9133. Bibcode:1986PNAS...83.9129D. 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. S2CID   26000048.
  9. ↑ 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. PMID   18605984. S2CID   1223977.
  10. ↑ 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. S2CID   44821306.
  11. ↑ Katzel JA, Fanucchi MP, Li Z (January 2009). "Recent advances of novel targeted therapy in non-small cell lung cancer". Journal of Hematology & Oncology. 2 (1): 2. doi:10.1186/1756-8722-2-2. PMC   2637898 . PMID   19159467.
  12. ↑ Lacroix M (2014). Targeted Therapies in Cancer. Hauppauge, NY: Nova Sciences Publishers. ISBN   978-1-63321-687-7.
  13. ↑ Jordan VC (January 2008). "Tamoxifen: catalyst for the change to targeted therapy". European Journal of Cancer. 44 (1): 30–38. doi:10.1016/j.ejca.2007.11.002. PMC   2566958 . PMID   18068350.
  14. ↑ Warr MR, Shore GC (December 2008). "Small-molecule Bcl-2 antagonists as targeted therapy in oncology". Current Oncology. 15 (6): 256–261. doi:10.3747/co.v15i6.392. PMC   2601021 . PMID   19079626.
  15. ↑ Li J, Zhao X, Chen L, Guo H, Lv F, Jia K, et al. (October 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.
  16. ↑ "Apatinib". clinicaltrials.gov.
  17. ↑ "Phase II study of AEZS-108 (AN-152), a targeted cytotoxic LHRH analog, in patients with LHRH receptor-positive platinum resistant ovarian cancer". 2010.
  18. ↑ Zhai B, Gobielewska A, Steino A, Bacha JA, Brown DM, Niclou S, Daugaard M (December 2016). "Molecular mechanisms of dianhydrogalactitol (VAL-083) in overcoming chemoresistance in glioblastoma". European Journal of Cancer. 69: S119. doi:10.1016/S0959-8049(16)32955-0.
  19. ↑ 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.
  20. ↑ "VAL-083 Clinical Trials". ClinicalTrials.Gov. U.S. National Institutes of Health.
  21. ↑ "Merck, Endocyte in Development Deal". dddmag.com. 25 April 2012.
  22. ↑ "Keytruda". National Cancer Institute. 2011-02-02.
  23. ↑ "Pembrolizumab Use in Cancer". National Cancer Institute. 2014-09-18.
  24. ↑ "Therascreen KRAS RGQ PCR Kit – P110030“. Device Approvals and Clearances. U.S. Food and Drug Administration. 2012-07-06.
  25. ↑ European medicines Agency (June 2014). “Erbitux® Summary of Product Characteristics (PDF).“ 2015-11-19.
  26. ↑ “Cetuximab (Erbitux). About the Center of Drug Evaluation and Research." U.S. Food and Drug Administration. 2015-11-16.
  27. ↑ "Merck KGaA: European Commission Approves Erbitux for First-Line Use in Head and Neck Cancer" 2015-11-16
  28. ↑ Pollack A (2009-03-31). "F.D.A. Panel Supports Avastin to Treat Brain Tumor". New York Times . Retrieved 2009-08-13.
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