A Tale of Two Receptors: Insulin and Insulin-Like Growth Factor Signaling in Cancer

摘要

Inhibition of the type I IGF receptor (IGF1R) has been the focus of numerous clinical trials. Two reports in this issue describe the results of phase I trials of an IGF1R tyrosine kinase inhibitor OSI-906. This commentary will describe the complex endocrine changes induced by these types of agents. In this issue of Clinical Cancer Research, two phase I studies of the type I insulin-like growth factor receptor (IGF1R) and insulin receptor inhibitor OSI-906 are presented (1, 2). In A Tale of Two Cities, Charles Dickens wrote, "we had everything before us, we had nothing before us." This phrase describes the past several years in the development of the IGF1R inhibitors. Fueled by abundant preclinical and population data implicating IGF1R in cancer biology, strategies to target this transmembrane tyrosine kinase inhibitor (TKI) were developed. A burst of clinical trials involving at least five mAbs and three TKIs directed against IGF1R were planned and completed. To date, the development of the IGF1R mAbs has largely ended. Although there was some evidence of single-agent activity, the majority of combination therapy trials were failures (reviewed in ref. 3). Initially, the most promising published phase II report of IGF1R combination therapy in non-small cell lung cancer was retracted due to errors in determining response. The recently reported phase III trials showed a trend toward harm for patients receiving chemotherapy and the IGF1R mAb figitumumab (4). Was IGF1R the right target? As the name suggests, "insulin-like" growth factors are highly related to insulin (Fig. 1A). Both the ligands and receptors have significant homology, yet we have tended to think of the two ligand and receptor systems as having separate physiologic roles. Insulin's role in glucose homeostasis is well understood. IGF-I regulates growth; it is produced at the time of puberty in response to pituitary release of growth hormone (GH). Thus, these two highly regulated endocrine systems have been linked to metabolism (insulin) and growth (IGF-I), but it is clear the two systems overlap in their physiologic functions. IGF-I dearly has metabolic functions and has been used to treat type 2 diabetes (5). Insulin enhances tumor growth in animal models of type 2 diabetes (6). In the development of the IGF1R mAbs, there was an intentional effort to avoid cross-reactivity with the insulin receptor to maintain glucose homeostasis.