Abstract
Over the last two decades, many studies have demonstrated that the insulin-like growth factor-1 (IGF-1) is involved in a number of patho-physiological processes, as well as in the development of different types of solid tumors, including breast cancer (BC). Preclinical and clinical data showed that IGF-1 receptor (R) is overexpressed and hyper-phosphorylated in several subtypes of BCs. The central implications of this pathway in tumor cell proliferation and metastasis make it an important therapeutic target. Moreover, the IGF-1 axis has shown strong interconnection with estrogen regulation and endocrine therapy, suggesting a possible solution to anti-estrogen resistance. IGF-1R might also interfere with other pivotal therapeutic strategies, such as anti HER2 treatments and mTOR inhibitors; several clinical trials are ongoing evaluating the role of IGF-1R inhibition in modulating resistance mechanisms to target therapies. Our aim is to offer an overview of the most recent and significant field of application of IGF-1 inhibitors and relevant therapeutic strategies, weighing their possible future impact on clinical practice.
Highlights
The insulin-like growth factor-1 (IGF-1) is an insulin-like protein with anabolic effects, whose production is stimulated by growth hormone (GH), and is one of the main mediators of GH effects
NVP-AEW541 is a small molecular weight pyrrolo-[2,3]-pyrimidine derivative kinase inhibitor of IGF-insulin receptor (IR) (García-Echeverría et al, 2004), while NVP-ADW742 is an ATP-competitive inhibitor that prevents IGF-IR phosphorylation (Warshamana-Greene et al, 2005). These two inhibitors have 15–30 fold increased potency for IGF-1R kinase inhibition compared to IR kinase inhibition in cellular assay, but they are able to distinguish between the IGF-IR and the closely related InsR (Mitsiades et al, 2004; Serra et al, 2008)
Several studies demonstrated that these tyrosine kinase inhibitors (TKIs) inhibit IGF-IR/IR phosphorylation and AKT activation, TABLE 1 | Key clinical trial targeting IGF-1 axis in solid tumors
Summary
The insulin-like growth factor-1 (IGF-1) is an insulin-like protein with anabolic effects, whose production is stimulated by growth hormone (GH), and is one of the main mediators of GH effects. High plasma levels of IGF-1 and IGFBP-3 represent a risk factor for the development and recurrence of BC in the general population (Key et al, 2010) This is verified for the incurrence of estrogen receptor positive (ER+) tumors, independent from menopausal status (Key et al, 2010). A pooled data analysis of 4790 cases from 17 prospective studies from 12 countries clearly showed that women with relatively high circulating IGF-1 had a 30% higher risk of BC than women with relatively low circulating IGF-1 This positive association was found in ER+ but not estrogen-receptor negative (ER−) tumors. Murphy et al (2020) in their observational and Mendelian randomization analyses with 430,000 women found evidence that supports a probable causal relationship between circulating IGF-1 concentrations and BC Mammographic density is another BC risk factor. Some findings suggest a positive correlation (Duggan et al, 2013), others an inverse (Kalledsøe et al, 2019), or no clear association of the biomarkers of the IGF system with all causes of mortality or BC-specific mortality and recurrence (Al-Delaimy et al, 2011; Hartog et al, 2013). Zhu et al (2020) in their large prospective study showed an inverse and independent association between circulating IGF-1 and all-cause mortality in invasive BC patients, with association being consistent across all clinical risk factors
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