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

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.

Abstract

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.

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Figure 1: The insulin and IGFI receptor family.
Figure 2: Perturbations of insulin and IGFI physiology by type 2 diabetes, metformin, IGF1R antibodies and PI3K inhibitors.
Figure 3: Proposed mechanisms of antineoplastic actions of biguanides.

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Acknowledgements

The author thanks L. Lui for valuable assistance in the manuscript preparation.

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Correspondence to Michael Pollak.

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M.P. has consulted for Pfizer, Novo Nordisk, Sanofi Aventis, Bristol Myers Squibb, Axelar and Boerringer Ingelheim, and has received research funding from Pfizer and Novo Nordisk.

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Glossary

C-peptide

Insulin is produced as preproinsulin that consists of an A-chain, a C-peptide, a B-chain and a signal sequence. The signal sequence is cleaved to produce proinsulin, and the C-peptide is cleaved leaving the A-chain and B-chain to form insulin.

Type 2 diabetes

Diabetes that initially arises as a result of insulin resistance in tissues such as the liver, muscle and fat, rather than through primary loss of β-islet cells in the pancreas.

Hyperinsulinaemia

High concentrations of insulin circulating in the blood.

Hyperglycaemia

High concentrations of glucose circulating in the blood.

Immortal time bias

This can occur in pharmacoepidemiology studies if determination of treatment status is carried out during a time interval that may, for some subjects, also represent part of the follow-up period for clinical end points.

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Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer 12, 159–169 (2012). https://doi.org/10.1038/nrc3215

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