From Single- to Multi-Target Drugs in Cancer Therapy: When Aspecificity Becomes an Advantage

• Published in: Current medicinal chemistry Vol. 15; no. 5; pp. 422 - 432
• Main Authors: PETRELLI, A, GIORDANO, S
• Format: Journal Article
• Language: English
• Published: Schiphol Bentham Science Publishers Ltd 01.02.2008; Bentham Science
• Subjects: Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzamides; Benzenesulfonates - therapeutic use; Bevacizumab; Biological and medical sciences; Cetuximab; Chemotherapy; Clinical Trials as Topic; Drug resistance; Enzyme Inhibitors - therapeutic use; Erlotinib Hydrochloride; Gefitinib; General aspects; Growth factors; Humans; Imatinib Mesylate; Indoles - therapeutic use; Inhibitors; Lapatinib; Leukemia; Medical sciences; Neoplasms - drug therapy; Neovascularization, Pathologic - drug therapy; Niacinamide - analogs & derivatives; Pharmacology. Drug treatments; Phenylurea Compounds; Piperazines - therapeutic use; Piperidines - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyridines - therapeutic use; Pyrimidines - therapeutic use; Pyrroles - therapeutic use; Quinazolines - therapeutic use; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Sorafenib; Subpopulations; Sunitinib; Trastuzumab; Antineoplastic agent; Vandetanib; Targeted therapy; Monoclonal antibody; Research and development; Bevacizumab; tyrosine kinase inhibitors; Signal transduction; cancer therapy; Sunitinib; Pertuzumab; Targeted drug; Lapatinib; Small molecule; Cetuximab; Gefitinib; Mechanism of action; Imatinib; Enzyme; Transferases; Enzyme inhibitor; Malignant tumor; Biological activity; Immunomodulator; Growth factor receptor; Treatment; Erlotinib; Sorafenib; Tyrosine kinase receptors; Trastuzumab; small molecules; Cancer; monoclonal antibodies
• ISSN: 0929-8673; 1875-533X
• DOI: 10.2174/092986708783503212

Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts on all dividing cells generating toxic effects and damage of normal tissues, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. Molecules controlling cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Two classes of compounds targeting RTKs are currently used in clinical practice: monoclonal antibodies and tyrosine kinase inhibitors. The era of targeted therapy began with the approval of Trastuzumab, a monoclonal antibody against HER2, for treatment of metastatic breast cancer, and Imatinib, a small tyrosine kinase inhibitor targeting BCR-Abl, in Chronic Myeloid Leukemia. Despite the initial enthusiasm for the efficacy of these treatments, clinicians had to face soon the problem of relapse, as almost invariably cancer patients developed drug resistance, often due to the activation of alternative RTKs pathways. In this view, the rationale at the basis of targeting drugs is radically shifting. In the past, the main effort was aimed at developing highly specific inhibitors acting on single RTKs. Now, there is a general agreement that molecules interfering simultaneously with multiple RTKs might be more effective than single target agents. With the recent approval by FDA of Sorafenib and Sunitinib - targeting VEGFR, PDGFR, FLT-3 and c-Kit - a different scenario has been emerging, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role.