Drugging IGF-1R in cancer: New insights and emerging opportunities

Abstract

The insulin-like growth factor (IGF) axis plays important roles in cancer development and metastasis. The type 1 IGF receptor (IGF-1R) is a key member in the IGF axis and has long been recognized for its oncogenic role in multiple cancer lineages. Here we review the occurrence of IGF-1R aberrations and activation mechanisms in cancers, which justify the development of anti-IGF-1R therapies. We describe the therapeutic agents available for IGF-1R inhibition, with focuses on the recent or ongoing pre-clinical and clinical studies. These include antisense oligonucleotide, tyrosine kinase inhibitors and monoclonal antibodies which may be conjugated with cytotoxic drug. Remarkably, simultaneous targeting of IGF-1R and several other oncogenic vulnerabilities has shown early promise, highlighting the potential benefits of combination therapy. Further, we discuss the challenges in targeting IGF-1R so far and new concepts to improve therapeutic efficacy such as blockage of the nuclear translocation of IGF-1R.

Keywords: Cancer; Combination therapy; IGF-1R; Metastasis; Targeted therapy.

Figure 1

Amplification of IGF1R copy number is frequent in several common types of human cancer. (A) The top 15 most frequent cancer types that have been reported to have IGF1R mutations or copy number variations (TCGA; n = 10,953). (B) Correlation of IGF1R copy number and mRNA levels in TCGA cancer patients (n = 9,889).

Figure 2

The sequence and the corresponding immunostimulatory functions of motifs within IMV-001, which is complementary to IGF1R. The sequence contains a CpG motif and a palindromic sequence, which stimulate innate immune responses upon recognized by toll-like receptor 9. Phosphorothioate modification promotes nuclease resistance and binding of AS-ODN to plasma proteins, thereby decreasing renal loss and enhancing tissue delivery. The modification may also induce immune activities.

Figure 3

Overview of the therapeutic strategies developed to inhibit IGF-1R signaling. The schematic shows the key components of the IGF axis and the four major approaches for IGF-1R inhibition: (1) by suppressing IGF-1R expression using antisense oligonucleotide (AS-ODN) or siRNA; (2) by blocking the binding of IGF-1R with ligands (IGF-1R monoclonal antibodies or IGF-1/-2 neutralizing antibodies); (3) by repressing IGF-1R kinase activity using tyrosine kinase inhibitor (TKI); and (4) by conjugating cytotoxic drug to IGF-1R antibody.