ABSTRACT
The insulin-like growth factor (IGF) system is emerging as a promising new target in cancer therapy. Experimental models and epidemiological studies have demonstrated that the IGF system plays a key role in malignant transformation and cancer progression. Different strategies are being pursued to target this pathway. Several monoclonal antibodies and tyrosine kinase inhibitors targeting the IGF-1 receptor are in clinical development. Early clinical trials indicate these drugs have acceptable safety profiles, and there is pharmacodynamic evidence that actual target inhibition is achievable in patients. Emerging efficacy data as single agent and in combination with chemotherapy is encouraging yet too early for firm conclusions. This manuscript reviews the role of the IGF system in human malignancy and its interactions with other signaling pathways, and summarizes the available data of IGF-1R inhibitors currently in clinical trials.
Subject(s)
Antineoplastic Agents/administration & dosage , Neoplasms/drug therapy , Somatomedins/antagonists & inhibitors , Somatomedins/physiology , Animals , Clinical Trials as Topic/methods , Drug Delivery Systems , Humans , Models, Biological , Neoplasms/genetics , Neoplasms/metabolism , Protein Kinase Inhibitors/therapeutic use , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/physiology , Somatomedins/genetics , Somatomedins/metabolismABSTRACT
The mitogenic signaling in mammalian cells is carried out mainly by growth factors that interact with receptors localized at the plasma membrane. Most of these receptors have a tyrosine kinase activity domain that is localized at the cytoplasmic region of the molecule. The interaction of the growth factors with the receptors, besides inducing the kinase activity of the receptor, activate signaling pathways the alter gene expression patterns and induce mitogenesis, or if deregulated are related to cancer. Among these receptors ERBB, VEGF, PDGF and IGF are attractive targets for directed therapies. ERBB receptors are frequently involved in the production of many types of cancers. Both, the over-expression of the growth factor and the receptor, besides mutations at the cytoplasmic tyrosine kinase domain contribute to constitutive signaling in human cancer. VEGF has a pivotal role in maintaining the tumor growth by facilitating growth of new blood vessels. Therefore, inhibition of tumor growth targeting of the tumor vasculature, by interfering with the activity of VEGFr is now a real alternative in combinatorial therapies. PDGF is a growth factor involved in growth of connective tissue and wound healing. Activating mutations of PDGFr have been found in gastrointestinal tumors and the autocrine signaling maintained by this receptor have been described in many tumors. Imatinib, and inhibitor of the tyrosine kinase activity of Bcr-Abl targets also the kinase of the PDGFr. Finally IGF-I an II have an important antiapoptotic and pro-mitogenic role in most tumors. Different inhibitors are now under clinical studies for the use in combination of chemotherapeutic drugs in the treatment of different tumors.
Subject(s)
Growth Substances/physiology , Receptor Protein-Tyrosine Kinases/physiology , Signal Transduction , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , ErbB Receptors/physiology , Genes, erbB , Genes, erbB-1 , Genes, erbB-2 , Humans , Ligands , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/physiology , Neoplasms/drug therapy , Neoplasms/physiopathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/physiopathology , Platelet-Derived Growth Factor/antagonists & inhibitors , Platelet-Derived Growth Factor/physiology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/physiology , Receptor, ErbB-3/antagonists & inhibitors , Receptor, ErbB-3/physiology , Receptor, ErbB-4 , Receptors, Somatomedin/antagonists & inhibitors , Receptors, Somatomedin/physiology , Signal Transduction/physiology , Somatomedins/antagonists & inhibitors , Somatomedins/physiology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/physiologySubject(s)
Abnormalities, Multiple/metabolism , Heparan Sulfate Proteoglycans , Heparitin Sulfate/physiology , Proteoglycans/physiology , Somatomedins/antagonists & inhibitors , Abnormalities, Multiple/genetics , Animals , Glypicans , Heparitin Sulfate/genetics , Insulin-Like Growth Factor II/antagonists & inhibitors , Mice , Mice, Knockout , Proteoglycans/genetics , SyndromeABSTRACT
This study was undertaken to define the interrelationships of somatomedin, growth hormone, and an inhibitor of SM in protein-calorie malnutrition. Twenty-seven patients, eight to 60 months of age, were studied. Twenty-one well-nourished children acted as controls. SM was significantly depressed at Days 2 and 8 (p less than 0.01) but was not different from controls at Day 29 and 50. In ten out of 27 Day 2 samples and six out of 27 Day 8 samples an inhibitor was identified. When SM values were compared to simultaneous hGH levels, there was an inverse relationship. The low SM levels in the face of markedly elevated hGH levels suggests a functional block in the synthesis and/or release of SM.