Present day cancer treatment is multidisciplinary and usually includes various combinations of surgery, chemotherapy and radiation therapy. In spite of various advances, these treatments are still associated with toxicity risks. This has lead to the development of a fourth type of treatment called Targeted Therapy. During the late 20th century, it was realised that mutations in proto-oncogene and deletion of tumor suppressor genes can lead to carcinogenesis. Targeted therapy employs small chemical molecules or other substances, such as monoclonal antibodies, to interfere with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells like in traditional chemotherapy . Molecular Targeted Therapy (MTT) has an advantage of high therapeutic index, high selectivity and low toxicity.
Types of Targeted Therapy:
Small molecule drugs: Small molecule drugs have the ability to pass through cell membranes including plasma membrane1. They can be used to interfere with specific areas of the target proteins located either outside or inside the cell, modify its enz activity or its interaction with other molecules and inhibit key signaling pathways that lead to carcinogenesis. These pathways include signal transduction via the activation of kinases, programmed cell death or “apoptosis”, regulation of gene transcription, or tumor angiogenesis. Imatinib was developed in the late 1990’s by biochemist Nicholas Lydon, oncologist Brian Drucker and Charles Sawyer. Imatinib (Gleevec) received FDA approval in May 2001 and was hailed by TIME magazine as the "magic bullet” that can cure cancer .Originally developed as a specific inhibitor of the bcr/abl tyrosine kinase that characterizes chronic myeloid leukemia (CML), this drug was subsequently found to inhibit the activity of several other tyrosine kinases, and the platelet-derived growth factor (PDGF) receptor. Imatinib inhibits these kinases by binding to the active site on the kinase molecule. Some kinases are required for the continued survival of cancer cells, and inhibition of these kinases results in the death of the cancer cells. Nilotinib and Dasatinib are second generation drugs that are currently in the last stage of clinical trials. Small molecules can be used not only to inhibit the function of cellular enzymes, but also to activate them like the Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL). TRAIL binds to and activates two distinct cell surface receptors called Death Receptor 4 (DR4) and Death Receptor 5 (DR5) and lead to the activation of pathways within the cell that ultimately lead to programmed cell death (apoptosis).
Monoclonal Antibodies: Monoclonal antibodies (MAbs) are created from a single cell type and act by recognizing the protein on the surface of the cell and then locking onto it2. Monoclonal antibodies can interfere with the interaction of signaling molecules with receptors on the outside of a cell which often activates pathways inside the cancer cell. Antibodies can be engineered to interact with very specific targets and so have a high degree of specificity which helps avoid unwanted side effects. Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphocytic leukaemia (CLL).
Angiogenesis Inhibitors: A theory proposed by surgeon Judah Folkman in 1971, that if the development of new blood vessels could be stopped, a tumor could not grow or spread, is the basis for research into antiangiogenic drugs. Interferon-alpha and Thalidomide are believed to have some ability to inhibit angiogenesis and are being studied in specific cancer types of cancers. Many antiangiogenesis agents are still under clinical trials and require FDA approval3 .
Therapeutic Cancer Vaccines: Cancer cells are not recognised by the body’s immune system and hence no immune response is mounted against them which leaves them to potentially develop into tumors. Some cancers suppress the body’s immune systems. Therapeutic cancer vaccines try to activate the body's immune system to make it recognize and attack cancer cells4. They are used on patients who are already undergoing treatment .The cancer vaccine may contain inactivated cancer cells, viruses that express tumor antigens, or any antigens that are overexpressed by cancer cells. An adjuvant, usually Interleukin-2 is used to induce a strong immune response.
Future of Targeted Theraphy: Presently targeted therapy is being used as an adjuvant therapy in the treatment of haematological malignancies, solid organ tumors, neuroendocrine tumors and breast cancer, along with the other classical chemo treatments. The continued research into this field might result in it being one of the mainstay treatment modality in future cancer treatment.
1. Peter Büchler.Organic synthesis toward small molecule probes and drug. Proc Natl Acad Sci U S A. 2011 April 26; 108(17): 6699–6702.
2. Cathy Eng.The Evolving Role of Monoclonal Antibodies In Colorectal Cancer. Oncologist. 2010 January; 15(1): 73–84.
3. Jie Ma, David J. Waxman. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol Cancer Ther. 2008 December; 7(12): 3670–3684.
4. Azam Bolhassani, Shima Safaiyan, Sima Rafati.Improvement of different vaccine delivery system for cancer therapy. Mol Cancer. 2011; 10: (3).
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