Understanding the Key to Targeting the IGF Axis in Cancer: A Biomarker Assessment

Abstract

Type 1 insulin like growth factor receptor (IGF-1R) targeted therapies showed compelling pre-clinical evidence; however, to date, this has failed to translate into patient benefit in Phase 2/3 trials in unselected patients. This was further complicated by the toxicity, including hyperglycemia, which largely results from the overlap between IGF and insulin signaling systems and associated feedback mechanisms. This has halted the clinical development of inhibitors targeting IGF signaling, which has limited the availability of biopsy samples for correlative studies to understand biomarkers of response. Indeed, a major factor contributing to lack of clinical benefit of IGF targeting agents has been difficulty in identifying patients with tumors driven by IGF signaling due to the lack of predictive biomarkers. In this review, we will describe the IGF system, rationale for targeting IGF signaling, the potential liabilities of targeting strategies, and potential biomarkers that may improve success.

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

“…Consequently, many drug development programs targeting the IGF-IR have been discontinued. Several possible explanations have been suggested for the failure of IGF-IR therapy, as reviewed in [187–189]. Firstly, most past clinical trials failed to incorporate the use of predictive biomarkers for the selection of probable responders.…”

The Influence of Exercise on the Insulin-like Growth Factor Axis in Oncology: Physiological Basis, Current, and Future Perspectives

“…The available literature does not allow for discrete conclusions to be made regarding the effects of specific exercise prescription, reflecting the need for continued development of this area to enhance our understanding of the IGF axis response to exercise. Although the pathophysiologic role of the IGF axis in tumor proliferation is well supported (54,73), the potential mediatory role of exercise therapy on this series of proteins remains unclear. Furthermore, it is worth noting the distinction between expression of the IGF axis in populations with current malignancy or postmalignancy.…”

“…To this end, exercise may be an effective targeted therapy by way of its physiologic potential to reduce systemic IGF ligands capable of IGF1R activation in conditions of overabundance without adversely affecting the anabolic role of this signaling in skeletal myocytes. In addition, IGF1R inhibitors have been suggested to be more effective treatments in cancers with select genotypes and phenotypes such as in KRAS-mutant (rather than wild-type) colorectal or lung cancers and triple-negative (rather than hormone receptor-positive) breast cancers (73,86). Future exercise trials assessing tumor-specific outcomes related to the IGF1R and its intracellular signaling pathways may also benefit from the inclusion of this type of distinction.…”

“…Alternative strategies include using monoclonal antibodies to reduce the bioavailability of ligands capable of initiating IGF1R signaling (73). To this end, exercise may be an effective targeted therapy by way of its physiologic potential to reduce systemic IGF ligands capable of IGF1R activation in conditions of overabundance without adversely affecting the anabolic role of this signaling in skeletal myocytes.…”

Estrogen Receptor-β and the Insulin-Like Growth Factor Axis as Potential Therapeutic Targets for Triple-Negative Breast Cancer

“…Ligand binding then activates the downstream mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B (PKB) pathways. 82 Although early phase clinical trials raised hope for the use of IGF1R-specific antibodies for cancer therapy, initial phase III results in unselected patients have not been effective. Further clinical studies may benefit from use of predictive biomarkers to identify probable responders, the use of rational combination therapies, and consideration of alternative targeting.…”