Defining the pathway to insulin-like growth factor system targeting in cancer

Abstract

The insulin-like growth factors (IGFs; IGF-1 and IGF-2) play central roles in cell growth, differentiation, survival, transformation and metastasis. The biologic effects of the IGFs are mediated by the IGF-1 receptor (IGF-1R), a receptor tyrosine kinase with homology to the insulin receptor (IR). Dysregulation of the IGF system is well recognized as a key contributor to the progression of multiple cancers, with IGF-1R activation increasing the tumorigenic potential of breast, prostate, lung, colon and head and neck squamous cell carcinoma (HNSCC). Despite this relationship, targeting the IGF-1R has only recently undergone development as a molecular cancer therapeutic. As it has taken hold, we are witnessing a robust increase and interest in targeting the inhibition of IGF-1R signaling. This is accentuated by the list of over 30 drugs, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) that are under evaluation as single agents or in combination therapies. The IGF-binding proteins (IGFBPs) represent the third component of the IGF system consisting of a class of six soluble secretory proteins. They represent a unique class of naturally occurring IGF-antagonists that bind to and sequester IGF-1 and IGF-2, inhibiting their access to the IGF-1R. Due to their dual targeting of the IGFs without affecting insulin action, the IGFBPs are an untapped "third" class of IGF-1R inhibitors. In this commentary, we highlight some of the significant aspects of and prospects for targeting the IGF-1R and describe what the future may hold.

Figure 1. The IGF System in Cancer

(a) IGF System Components. Shown are the ligands, IGF-1/IGF-2, the receptors, IGF-1R, IR-A, IR-B and hybrid IGF-1R:IR-A and IGF-1R:IR-B receptors and IGFBPs. The mAbs and TKIs targeting the IGF-1R is an incomplete list. (1b) Targeting the Tumor Microenvironment IGF System. Within the tumor microenvironment, multiple cell types secrete IGF-1 that diffuses to tumor cells to enhance tumorigenesis. IGFBP inhibition of IGF-1 and IGF-2 is well suited for the tumor microenvironment where multiple sources of IGF-1 exist. Also shown is increased angiogenesis mediated by VEGF downstream of IGF-1R action [99, 102, 103].

Figure 1. The IGF System in Cancer

(a) IGF System Components. Shown are the ligands, IGF-1/IGF-2, the receptors, IGF-1R, IR-A, IR-B and hybrid IGF-1R:IR-A and IGF-1R:IR-B receptors and IGFBPs. The mAbs and TKIs targeting the IGF-1R is an incomplete list. (1b) Targeting the Tumor Microenvironment IGF System. Within the tumor microenvironment, multiple cell types secrete IGF-1 that diffuses to tumor cells to enhance tumorigenesis. IGFBP inhibition of IGF-1 and IGF-2 is well suited for the tumor microenvironment where multiple sources of IGF-1 exist. Also shown is increased angiogenesis mediated by VEGF downstream of IGF-1R action [99, 102, 103].

Figure 2. IGFBP Structures Obtained by NMR or X-ray Crystallography

(a) 3D structure of the N-terminal domain of IGFBP-4 (PDB code: 2DSP) and (b) the C-terminal domain of IGFBP-2 (PDB code: 2H7T). (c) Also shown is a ternary complex involving the N-and C-terminal domains of IGFBP-4 with IGF-1 (PDB code: 2DSR).