Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug

Abstract

The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signaling and compensatory signaling by the insulin receptor (IR) isoform A that can bind IGF-II and initiate mitogenic signaling. Here we briefly review the current state of IGF-targeting biologicals, discuss some factors that may be responsible for their poor performance in the clinic and outline the stepwise bioengineering and validation of an IGF-Trap—a novel anti-cancer therapeutic that could bypass these limitations. The IGF-Trap is a heterotetramer, consisting of the entire extracellular domain of the IGF-IR fused to the Fc portion of human IgG1. It binds human IGF-I and IGF-II with a three-log higher affinity than insulin and could inhibit IGF-IR driven cellular functions such as survival, proliferation and invasion in multiple carcinoma cell models in vitro. In vivo, the IGF-Trap has favorable pharmacokinetic properties and could markedly reduce metastatic outgrowth of colon and lung carcinoma cells in the liver, outperforming IGF-IR and ligand-binding monoclonal antibodies. Moreover, IGF-Trap dose-response profiles correlate with their bio-availability profiles, as measured by the IGF kinase receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. Our studies identify the IGF-Trap as a potent, safe, anti-cancer therapeutic that could overcome some of the obstacles encountered by IGF-targeting biologicals that have already been evaluated in clinical settings.

TMS-Induced Controlled BBB Opening: Preclinical Characterization and Implications for Treatment of Brain Cancer

“…The IGF axis consists of the IGF-I receptor and its high-affinity binding ligands IGF-I and IGF-II. These agents have been implicated in all stages of cancer growth and progression [ 37 , 55 , 56 , 57 , 58 ], as well as in the regulation of tumor microenvironment, and identified as prognostic markers and therapeutic targets in brain tumors such as glioblastoma multiforme. Our findings indicate the ability of rTMS to generate BBB opening to an anticancer pharmaceutical and imply that anticancer treatment can be coupled to TMS to achieve increased efficacy.…”

“…The fluorescent tracer succinimidyl ester (NHS, 1 mg/mL in dimethyl sulfoxide, Thermo Fisher Scientific Ltd., Waltham, MA, USA) was conjugated in vitro to IGF-Trap (Trap 3.3, ~400 KDa) [ 37 ] by way of noncovalent interaction. Briefly, the protein was diluted in phosphate buffered saline (PBS) and was added with carbonate buffer (pH = 9.3) at a ratio of 1:9 (in favor of protein).…”

Single-Walled Carbon Nanohorns as Promising Nanotube-Derived Delivery Systems to Treat Cancer

“…Insulin-like growth factor-1 receptor (IGF-1R) also plays a very important role in tumorigenesis since it is involved in stimulating tumor growth and prevents apoptosis. Furthermore, it is overexpressed in many types of malignances such as breast, prostate, liver and glioblastoma cancers [ 91 , 92 , 93 , 94 ]. Therefore, IGF-1R could be potentially a cancer targeting molecule.…”

Levels of the IGF system components in malignant lesions of the lungs with preventive effect of 1,3-diethylbenzimidazolium triiodide in the experiment

“…Предполагают, что IGF-I способен индуцировать ЭМП при раке [3]. Вся система IGF представлена двумя лигандами: IGF-I и IGF-II; двумя рецепторами клеточной поверхности: IGF-IR и IGF-IIR; несколькими белками с высокой аффинностью связывания IGF: IGFBP 1-6 и протеазами [4,5].…”