Rationale and clinical results of multi-target treatments in oncology.
During the last 10 years, the concept of targeted biological therapy for the treatment of cancer has emerged. Targeted agents entered clinical practice only recently, and the first drugs with demonstrated clinical efficacy were mainly inhibitors of the ErbB family of receptors (i.e., EGFR and HER-2), either monoclonal antibodies (MAbs) or tyrosine kinase inhibitors (TKIs). After the proof of concept for the clinical efficacy and tolerability of these selective agents, it was conceived that most tumors will depend on more than one signaling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signaling pathways or multiple steps in the same pathway, either by the development of multi-targeted agents or the combination of single targeted drugs. The recent FDA and EMEA approval of sorafenib and sunitinib, both multi-targeted TKIs, marked the coming of age of this new generation of drugs. Now a whole new wave of multi-targeted compounds is moving into clinical trials, raising in the minds of investigators important questions about the best strategies to pursue in their use and many doubts about their differences and the seeming redundancies in the pipelines of pharmaceutical companies. This review will deal with the rationale underlying the multi-targeted approach and with the available clinical experience with multi-targeted agents, especially focusing on molecules with anti- EGFR mechanisms of action.
Sartore-Bianchi
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The Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, Milan, Italy. andrea.sartorebianchi@ospedaleniguarda.it
Ricotta
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Cerea
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Maugeri
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Siena
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D000077784:Axitinib; D001557:Benzenesulfonates / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007191:Indazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D000077341:Lapatinib; D009025:Morpholines / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010793:Phthalazines / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011687:Purines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D000077157:Sorafenib; D000077210:Sunitinib
D000077784:Axitinib; D001557:Benzenesulfonates; D066246:ErbB Receptors; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D000077341:Lapatinib; D009025:Morpholines; D009536:Niacinamide; D010671:Phenylurea Compounds; D010793:Phthalazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011687:Purines; D011725:Pyridines; D011758:Pyrroles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D000077157:Sorafenib; D000077210:Sunitinib; C404768:vatalanib; C420268:Canertinib; C489254:AEE 788; C452423:vandetanib