Edited by: Antonino Belfiore, University Magna Graecia of Catanzaro, Italy
Reviewed by: Giovanni Vitale, Universita degli Studi di Milano, Italy; Naoyuki Kataoka, Kyoto University School of Medicine, Japan
Specialty section: This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The insulin-like growth factor type 1 receptor (IGF-1R) plays a key role in the development and maintenance of cancer. Since the first links between growth factor receptors and oncogenes were noted over three decades ago, targeting the IGF-1R has been of great interest. This review follows the progress from inception through intense pharmaceutical development, disappointing clinical trials and recent updates to the signaling paradigm. In light of major developments in signaling understanding and activation complexities, we examine reasons for failure of first line targeting approaches. Recent findings include the fact that the IGF-1R can signal in the absence of the ligand, in the absence of kinase activity, and utilizes components of the GPCR system. With recognition of the unappreciated complexities that this first wave of targeting approaches encountered, we advocate re-recognition of IGF-1R as a valid target for cancer treatment and look to future directions, where both research and pharmaceutical strengths can lend themselves to finally unearthing anti-IGF-1R potential.
In 1983, two independent groups published their observations of sequence homology between an oncogene (Simian sarcoma virus oncogene,
The pivotal discovery in 1993 that mouse embryonic fibroblasts derived from embryos with a targeted disruption (homologous recombination) of the IGF-1R genes, named R-cells (
As antisense strategies do not work in humans, several approaches were undertaken in the late 1990s to target the IGF-1R in anti-cancer therapeutics, and with strong pre-clinical evidence multiple trials commenced. Over 30 drug candidates were developed and numerous clinical trials commenced (for current and regularly updated numbers see
Many have postulated the reasons why anti-IGF-1R agents failed to live up to their hype (reviewed in (
Along with cellular complexity outsmarting mono-therapy, it must be highlighted that the IGF-1R pharmaceutical race was different from others in its patient selection strategy. When viewed alongside the success stories in RTK therapeutics (e.g., HER2, C-kit therapeutics), the lack of any sort of patient selection, stratification or follow-up biomarker for therapeutic efficacy response in the case of IGF-1R, could very well have been a reason for failure. The flourish of excitement that a wonder drug lays within grasp hid the rational and well accepted need for careful patient selection. The IGF-1R trials included not only a wide range of cancer types, but also a broad range of molecular determinants and pre-trial treatment regimens (
Whilst the canonical signaling schematics of the IGF-1R depict a ligand binding induced signaling cascade down through the MAPK and Akt pathways, it has long been recognized that intracellular signaling is much more network orientated than linear (Figure
Alongside the explosion of interest in other aspects of cell biology, the non-coding-RNA regulation surrounding and controlling IGF-1R components is beginning to be pieced together. RNAs such as microRNAs and long-non-coding RNAs implement a further level of regulation around signaling pathways. This kind of regulation is illustrated in other pathways, such as p53 where a microRNA feedback circuitry has been identified and implicated in the pathogenesis of B-cell lymphocytic leukemia (
A major recent advancement in IGF-1R biology is the challenge to the RTK functionality (
In the field of GPCR biology, the paradigm of biased agonism is now fully accepted and describes the process by which a ligand:receptor pairing can selectively activate various downstream signaling pathways preferentially or to different degrees (
Unappreciated complexity, through the existence of plasma IGF-1R, hybrid receptors, pathway crosstalk, GPCR signaling components, RNA pathway regulation, lack of biomarkers, to name but a few, swamps the simple anti-IGF-1R targeted therapies in obvious failure (
In the early days of growth factor and oncogene research, in 1988, a 22-year long study commenced following a particularly interesting group of patients, to investigate the role of IGF-1R in aging, diabetes and cancer development (
All postulations ultimately underline the fact that anti-IGF-1R therapeutic strategies were overly simplistic and insufficient to have any grand therapeutic effect given the complexity of the system. Whilst reductionist box-to-box schematics of signaling pathways are undeniably useful in the molecular and cell biology classroom, we must also to be aware that they are impossibly simplistic. Basic research requires simplistic beginnings, but if we intend to translate these findings into therapeutics, the limitations and realistic utility of these simple schemes must be appreciated, something that may not have been fully realized in the IGF-1R story.
The future of IGF-1R therapeutics may still lie ahead in much smarter designed, second/third generation targeting that recognizes and complements the true complexity of the system. To take advantage of those few success cases within the clinical trials, research effort into biomarkers will be of critical importance. Biased agonists, which specifically select a subset of signaling downstream of a given receptor have come into play largely in the field of GPCR therapeutics, the largest therapeutically targeted biological agents of all drugs in use clinically (
With the combination of academia’s unearthing of the true signaling complexities, and pharmaceutical industry’s drug development and trial expertise, we may just witness a re-awakening of shared interest and a re-writing of the tale, and just maybe the Tortoise and the Hare will finish the race together.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Research support: Swedish Research Council, Swedish Cancer Society, Children Cancer Society, Crown Princess Margareta’s Foundation for the Visually Impaired, Welander Finsen Foundation, King Gustaf V Jubilee Foundation, Stockholm Cancer Society, the Stockholm County and Karolinska Institutet.