11 - The insulin–insulin-like growth-factor receptor family as a therapeutic target in oncology

Summary

Background

Insulin and insulin-like growth factors (IGFs) are potent mitogens, and the hypothesis that their receptors are important therapeutic targets in oncology has received considerable attention (reviewed in 1–5). In the last decade, more than 20 drug candidates that target IGF receptors or both insulin and IGF receptors have been developed. Of these, at least 12 have been taken forward to clinical trials.

The rationale for drug development in this area included clinical and epidemiologic evidence (for example 6,7) that circulating levels of insulin and/or IGFs are related to cancer risk and/or cancer prognosis, as well as laboratory studies (for example 8) which demonstrated that interfering with signaling had inhibitory effects on neoplastic behavior. Seminal studies (9) from the laboratory of Renato Baserga showing a requirement for presence of the IGF-I receptor for transforming activity of a variety of oncogenes also contributed to the rationale. This research was followed by laboratory studies of drug candidates that demonstrated activity (for examples 1,2,4,5), which then led to clinical trials. In retrospect, however, it must be recognized that most pre-clinical studies of drug candidates showed benefit in experimental cancer models engineered to be IGF-IR driven, or in models chosen specifically because they were sensitive to the drugs, with relatively little attention being given to studies of tumor or host characteristics that predicted activity.