Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: Lessons from the first clinical trials

Abstract

The insulin-like growth factor-I receptor (IGF-IR) was first cloned in 1986. Since then, intense work has defined classic phosphorelays activated via the IGF-IR, which regulate cell proliferation, apoptosis, motility, and fate. The understanding of the roles of hormones in cancer and the growth hormone–IGF–IGF-binding protein axis specifically has yield to a second wave of development: the design of specific inhibitors that interrupt the signaling associated with this axis. The ability to manipulate these pathways holds not only significant therapeutic implications but also increase the chance of deeper insight about the role of the axis in carcinogenesis and metastasis. Nowadays, >25 molecules with the same goal are at different stages of development. Here, we review the clinical and preclinical experience with the two most-investigated strategies, tyrosine kinase inhibitors and monoclonal antibodies, and the advantages and disadvantages of each strategy, as well as other alternatives and possible drug combinations. We also review the bio-markers explored in the first clinical trials, the strategies that have been explored thus far, and the clinical trials that are going to explore their role in cancer treatment.

MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells

“…Although mutation in the PTEN gene in RCC has been reported, it is not common, and its expression is also heterogeneous in different renal cancer cells (77,78). One mechanism of Akt kinase activation in RCC could involve activation of growth factor receptors (14,15). Our results demonstrate that both ACHN and 786-O renal cancer cells irrespective of their VHL status possess increased levels of IGF-1R compared with the normal kidney epithelial cells (Fig.…”

“…Several clinical trials used IGF-1R-specific antibody therapy. However, due to the presence of hybrid receptors containing IGF-1R and insulin receptor, the down-regulation of the receptor molecules resulted in adverse events in many studies, including hyperglycemia (14). Other preclinical strategies involved development of tyrosine kinase inhibitors.…”

“…Other preclinical strategies involved development of tyrosine kinase inhibitors. Due to 95% sequence homology in the ATP binding domains of IGF-1R and insulin receptor, it has been a challenge to develop specific tyrosine kinase inhibitors for IGF-1R (14). In this study, we have identified an miRNA, miR-214, which acts as an endogenous inhibitor of IGF-1R protein expression in renal cancer cells.…”

“…Receptor-bound IRS protein serves as docking sites for the Src homology 2 domain-containing proteins, which trigger signal transduction to induce tumor growth of RCC mainly by two arms, the Ras/MAPK and phosphatidylinositol 3-kinase/Akt pathways (14,15). Because of significant homology between IGF-1R and insulin receptor, they can form a hybrid receptor, which binds IGF-1 with an affinity similar to that with IGF-1R heterotetramer alone, and can elicit mitogenic signal transduction in tumor cells (14,15). Therefore, expression of these receptors in the RCC and availability of the ligands will influence the process of tumorigenesis.…”

Statin induces apoptosis of human colon cancer cells and downregulation of insulin-like growth factor 1 receptor via proapoptotic ERK activation

“…In normal cells, the IGF-1/IGF-1R system is regulated by multiple steps (5). The expression of growth hormone (GH) is activated by GH-releasing hormone (GHRH).…”