Molecular Pathways: Clinical Applications and Future Direction of Insulin-like Growth Factor-1 Receptor Pathway Blockade

Abstract

The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is a complex and tightly regulated network which is critical for cell proliferation, growth, and survival. IGF-1R is a potential therapeutic target for patients with many different malignancies. This brief review summarizes the results of clinical trials targeting the IGF-1R pathway in patients with breast cancer, sarcoma, and non-small cell lung cancer (NSCLC). Therapeutic agents discussed include both monoclonal antibodies to IGF-1R (dalotuzumab, figitumumab, cixutumumab, ganitumab, R1507, AVE1642) and newer IGF-1R pathway targeting strategies including monoclonal antibodies to IGF-1 and IGF-2 (MEDI-573 and BI 836845) and a small molecule tyrosine kinase inhibitor of IGF-1R (OSI-906). The pullback of trials in patients with breast cancer and NSCLC based on several large negative trials is noted and contrasted with the sustained success of IGF-1R inhibitor monotherapy in a subset of patients with sarcoma. Several different biomarkers have been examined in these trials with varying levels of success, including tumor expression of IGF-1R and its pathway components, serum IGF ligand levels, alternate pathway activation, and specific molecular signatures of IGF-1R pathway dependence. However, there remains a critical need to define predictive biomarkers in order to identify patients who may benefit from IGF-1R directed therapies. Ongoing research focuses on uncovering such biomarkers and elucidating mechanisms of resistance, as this therapeutic target is currently being analyzed from the bedside to bench.

IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma

“…Our data confirm that HER2 is frequently mutated in PILC and support previous suggestions that PILC tumors that do not have HER2 amplification should undergo sequencing to identify patients who would be responsive to HER2-targeted therapies (32). Previous trials of drugs that target IR or IGF1R signaling have led to disappointing results for many different cancers, including breast cancer, and better biomarkers for selecting patients who would be responsive to these agents are needed (33,34). IRS2 copy number gains were previously shown to enhance the sensitivity of CRC cells to IR/IGF1R inhibition (35).…”

Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells

“…The IGF1 pathway comprises three receptor tyrosine kinases [IGF-1R, insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor (IR)], three ligands (insulin, IGF-1, and IGF-2), and six serum insulin-like growth factor binding proteins (IGFBPs), which are important regulators of this pathway (20). This pathway can enhance the proliferation and development of cells by initiating the anti-apoptotic PI3K/Akt/mTOR and the mitogenic Ras/Raf/Mek/Erk pathways (21,22).…”

Compounds from the marine sponge Cribrochalina vasculum offer a way to target IGF-1R mediated signaling in tumor cells

“…The insulin growth factor-1 receptor (IGF- 1R), is another transmembrane receptor with tyrosine kinase activity found in NSCLC and other tumor types [14–18]. IGF-1R is found in cells as a tetramer with two extracellular localized α domains which are responsible for associating with ligand and two β subunits which apart from ligand binding also harbor the active kinase pocket [14–18].…”

“…IGF-1R is found in cells as a tetramer with two extracellular localized α domains which are responsible for associating with ligand and two β subunits which apart from ligand binding also harbor the active kinase pocket [14–18]. The β subunits also harbor docking sites for different adaptor proteins which subsequently control downstream kinase signaling such as MAPK and Akt signaling [14–18]. IGF-1R can bind its natural ligands IGF-1 and IGF-2 either as a homodimer or as a heterodimer with Insulin receptor A/B (InsR A/B).…”

“…IGF-1R can bind its natural ligands IGF-1 and IGF-2 either as a homodimer or as a heterodimer with Insulin receptor A/B (InsR A/B). In the latter complex, also insulin can act as ligand but with alteration in IGF-1-regulated signaling cascades as the major outcome (reviewed in [14, 15]).…”