The rationale and development of therapeutic insulin-like growth factor axis inhibition for lung and other cancers

The insulin-like growth factor (IGF) axis involves elements of endocrine, paracrine, and autocrine control. It is centrally involved in normal development and growth. Core signaling is driven through the IGF-1 receptor (IGF-1R) in either homo-multimeric complexes or hetero-multimeric complexes with the insulin receptor (IR). Signaling is affected by a large number of upstream and downstream factors, including the differential expression of various intracellular IR substrates, a range of stimulatory ligands (insulin, IGF-1, and IGF-2), the expression of specific clearance receptors (eg, IGF-2R), and different IGF-binding proteins. Considerable evidence exists to implicate aspects of the IGF axis in the development and maintenance of many different nonneoplastic and neoplastic diseases, including both small-cell lung cancer and non-small-cell lung cancer (NSCLC). A large number of different anticancer strategies directed against the IGF axis are being developed. Monoclonal antibodies directed against the IGF-1R are the furthest advanced clinically. Hyperglycemia appears to be a class effect. To date, the major difference among the antibodies used in clinical trials seems to be their plasma half-lives, leading to a number of different administration regimens being taken forward. Early signals of monotherapy activity have been notably reported in patients with Ewing sarcoma and in several other cancers. Encouraging increases in the NSCLC response rate have already been reported after the addition of an anti-IGF-1R antibody to first-line carboplatin and paclitaxel. Explorations of aspects of ligands, binding proteins, receptors, and receptor substrates are all ongoing to identify potential biomarkers predictive of benefit from IGF axis intervention.