Targeting the Insulin-like Growth Factor Axis for the Development of Novel Therapeutics in Oncology

Abstract

Insulin-like growth factors (IGF) are polypeptide hormones with potent anabolic and mitogenic effects that regulate cell growth and differentiation. Dysregulation of the IGF axis has been well documented in the development and progression of multiple types of cancer. As a result, compounds targeting the IGF axis have become an area of intense preclinical and clinical research for cancer therapeutics. The IGF axis is intimately involved with the insulin-signaling pathway because of their close homologies. This homology may explain hurdles encountered in the clinical development of IGF-targeted therapies, such as less-than-expected antitumor efficacy that may arise from compensatory increases in the activity of insulin receptor isoform A (IR-A), in response to IGF-I receptor (IGF-IR) inhibition and perturbations in glucose homeostasis, arising from the inhibition of insulin receptor isoform B (IR-B) activity. In this brief review, we compare differentiating factors that characterize the 3 major classes of IGF-targeting compounds: therapeutic antibodies that target IGF-IR, small molecule tyrosine kinase inhibitors that inhibit kinase activities of IGF-IR and IR, and antibodies that target IGF ligands. Cancer Res; 72(1); 3-12. Ó2012 AACR.

A Phase I Study of Continuous Oral Dosing of OSI-906, a Dual Inhibitor of Insulin-Like Growth Factor-1 and Insulin Receptors, in Patients with Advanced Solid Tumors

“…The binding of its cognate ligands, insulin-like growth factor-1 (IGF1) and -2 (IGF2), activates the intrinsic tyrosine kinase activity of IGF1R, resulting in its autophosphorylation and recruitment of the downstream signaling protein insulin receptor substrate (IRS) to the cell membrane, which subsequently activates both phosphoinositide 3-kinase-Akt and the MAPK pathways (1). IRS protein also mediates the activity of insulin receptor (IR), which shares 60% homology (1) with IGF1R.…”

From fever to immunity: A new role for IGFBP‐6?

“…IGFs in general and IGF‐II in particular are involved in promoting tumour growth in situ in an autocrine or paracrine fashion once the tumour has been established. Many cancers overexpress IGF2 59 by mechanisms including loss of imprinting (LOI) and loss of heterozygosity (LOH) 60, 61. Interestingly, other observations indicate that the IGF system might be important also for tumour cell death.…”

Targeting Human Cancer Stem Cells with Monoclonal Antibodies

“…Deregulation of IGF signaling has been widely demonstrated in the development and progression of multiple types of human cancer, consequently leading to the development and validation of therapeutics that target IGF signaling [149,150]. Various humanized recombinant mAb targeting the insulin-like growth factor receptor I (anti-IGF-IR), a transmembrane tyrosin kinase receptor for IGF-I and IGF-II that is overexpressed in many cancers [151,152], have been developed and tested in phase I-III clinical studies, alone or in combination with conventional cytostatic drugs and novel tumortargeted drugs [150].…”

“…Various humanized recombinant mAb targeting the insulin-like growth factor receptor I (anti-IGF-IR), a transmembrane tyrosin kinase receptor for IGF-I and IGF-II that is overexpressed in many cancers [151,152], have been developed and tested in phase I-III clinical studies, alone or in combination with conventional cytostatic drugs and novel tumortargeted drugs [150]. Although some IGF-IR-targeting mAbs, including figitumumab (CP-751.871), cixutumumab (IMC-A12), dalotuzumab (MK-0646), ganitumab (AMG-479), BII022 and AVE1642 showed rather disappointing results in clinical studies [150,[153][154][155][156], AVE1642 and figitumumab have recently been demonstrated to target human colon CSCs in vitro and in xenograft mice [157,158].…”

“…Figitumumab (CP-751,871) is a fully human IgG2 mAb against the IGF-IR that have been tested in phase I-III clinical trials in patients with non-small cell lung cancer and other solid tumors with a rather disappointing outcome, leading to the discontinuation of two phase III trials due to insufficient clinical activity of the antibody [150,[160][161][162]. Despite its rather weak anticancer activity in human solid tumors, figitumumab inhibited IGF-IR signaling, IGF-IR-induced Akt activation and growth of colon CSCs with enhanced IGF signaling that were enriched from human colon cancer cell lines [158].…”