The insulin and insulin-like growth factor receptor family in neoplasia: an update

• Published in: Nature reviews. Cancer Vol. 12; no. 3; pp. 159 - 169
• Main Author: Pollak, Michael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2012; Nature Publishing Group
• Subjects: 692/53/2423; 692/699/67; 692/699/67/1059; Animals; Antibodies; biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Clinical trials; Clinical Trials as Topic; Diabetes mellitus; Humans; Insulin; Insulin - metabolism; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factor I receptors; Insulin-like growth factor receptors; Insulin-like growth factors; Metformin; Multigene Family; Neoplasia; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Obesity; Prognosis; Protein-tyrosine kinase; Receptors, Somatomedin - genetics; Receptors, Somatomedin - metabolism; review-article; Reviews; Signal Transduction
• ISSN: 1474-175X; 1474-1768; 1474-1768
• DOI: 10.1038/nrc3215

Key Points Preclinical evidence for a role of insulin and insulin-like growth factor (IGF) signalling in promoting neoplastic growth is impressive. Several different targeting strategies for the insulin and IGFI receptor family exist, and dozens of drug candidates have shown activity in model systems. Phase III clinical trials have so far been undertaken only with IGFI receptor-specific antibodies. Although the final results have not yet been published, disappointing reports have been presented for some of these trials. Future trials may differ by incorporating predictive biomarkers, by using rational combination therapy approaches and by using other pharmacological approaches to targeting, such as anti-ligand antibodies or tyrosine kinase inhibitors. The insulin and IGFI receptor family may be involved in resistance mechanisms to therapies that target other signalling nodes in cancer cells, suggesting that there may be situations in which co-targeting will confer benefit. The insulin and IGFI receptor family is now known to have a role in the important relationships between macronutrient intake and cancer, diabetes and cancer, and obesity and cancer. Biguanides, such as metformin, which is widely used in diabetes treatment, have been reported in hypothesis-generating retrospective population studies of subjects with diabetes to be associated with reduced cancer burden. These agents lower insulin levels if they are increased, and have a variety of effects on cellular signalling and cellular metabolism. However, there are gaps in knowledge related to their pharmacokinetics and mechanisms of action that require elucidation. This Review reflects on the recent disappointing initial results from Phase III trials of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, and discusses the next steps in targeting insulin and IGFI signalling in cancer therapy. Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K–AKT pathway inhibitors.