OSI 930 is an inhibitor of the receptor tyrosine kinases c Kit

by Selleckchem | Nov 08 2013

The insulin-like growth factor 1 pathway is a complex and highly regulated system that is important in human growth and development . In human cancers, multiple components of this system become dysregulated and provide growth and survival advantages to tumor cells . In particular, the IGF-1 system has been implicated in OSI-930 the development and growth of several cancers, including breast, prostate and colon . It has also been identified as a mechanism by which the tumors evade death by several important anti-cancer therapies including cytotoxic chemotherapy, hormonal therapy, receptor tyrosine kinase inhibitor therapy, and radiation therapy . Since the IGF-1 pathway is active in the majority of solid and hematological malignancies, targeting this system has been an area of increasing drug development interest. In targeting the IGF-1 system, there are multiple key components that must be considered . Central to the system are it two VX-702 stimulatory ligands, IGF-1 and IGF-2. These circulating ligands provide proliferative and pro-survival signaling through their binding to the receptor tyrosine kinases, IGF-1 receptor and the insulin receptor . The affinity of IGF-1R and InsR for the binding of IGF-1 and -2, as well as the metabolic counterpart, insulin, is dependent on the presence hybrid IGF-1R/InsR pairs, as well as the isoform of InsR. Specifically, the fetal form or isoform A of the InsR has proliferative and prosurvival effects upon binding IGF-2, while the metabolic InsR isoform B has sub-physiologic binding affinity for any ligand except insulin . Additionally, a non-signaling membrane receptors, IGF-2 receptor VEGFR , binds and internalizes IGF-2, serving as a regulatory sink for this stimulatory ligand . Furthermore, the stimulatory effects of IGF-1 and -2 are further regulated by circulating IGF binding proteins 1 through 6 . IGFBPs, which vary in the binding affinities for IGF-1 and -2, limit the bioavailability of these ligands for receptor binding. There are a number of potential strategies by which to target and inhibit the IGF-1 system which have been reviewed elsewhere . However, a few strategies have emerged that are clinically feasible and are under early preclinical and clinical investigations. Monoclonal antibodies targeting the IGF-1R are currently being investigated in phase I and II clinical trials. IGF-1Rmab is an attractive strategy, as it targets the major proliferative kinase in the IGF-1 system and has little affinity for the InsR. Early clinical investigations with IGF-1Rmab??s suggest that IGF-1Rmab are very well tolerated and have shown early evidence of clinical activity . A potential liability to this strategy is that the mitogenic InsR isoform A is not targeted. Tyrosine kinase inhibitors of the IGF-1 system are also in preclinical and clinical development. Due to the nearly identical kinase domain of the IGF-1R and InsR, small molecules inhibitors have been developed that can completely block IGF-1 signaling through IGF1-R and InsR . However, the potential liability with this strategy is that TKIs may lead to hyperglycemia by blocking the InsR isoform B. The first clinical report of the phase I trial with the IGF-1Rmab, CP-751,871, in fact, reported hyperglycemia as this most common adverse event suggestion some interference with the function of InsR. As these agents are developed clinically, the mechanisms of resistance to IGF-1R targeting by TKIs or IGF-1Rmab will be important to understand as it can open new therapeutic strategies for the treatment of patients with cancer. Previous data suggested that IGF-1R signaling can provide a mechanism of resistance to HER receptor targeted therapy .