The role of insulin-like growth factors in the development of prostate cancer

ABSTRACT

Introduction

Preclinical, clinical, and population studies have provided robust evidence for an important role for the insulin-like growth factor (IGF) system in the development of prostate cancer.

Areas covered

An overview of the IGF system is provided. The evidence implicating the IGF system in the development of prostate cancer is summarized. The compelling evidence culminated in a number of clinical trials of agents targeting the system; the reasons for the failure of these trials are discussed.

Expert opinion

Clinical trials of agents targeting the IGF system in prostate cancer were terminated due to limited objective clinical responses and are unlikely to be resumed unless a convincing predictive biomarker is identified that would enable the selection of likely responders. The aging population and increased screening will lead to greater diagnosis of prostate cancer. Although the vast majority will be indolent disease, the epidemics of obesity and diabetes will increase the proportion that progress to clinical disease. The increased population of worried men will result in more trials aimed to reduce the risk of disease progression; actual clinical endpoints will be challenging and the IGFs remain the best intermediate biomarkers to indicate a response that could alter the course of disease.

KEYWORDS:

• Prostate cancer
• IGFs
• IGF-IR
• blocking antibodies
• tyrosine kinase inhibitors
• clinical trials

Article highlights

• The IGF system plays an important role in prostate cancer development. Evidence, particularly from population studies, indicates that the most important effect may be early in the progression from indolent disease to clinical cancer. This helps explain the lack of objective clinical responses in trials largely performed in men with advanced disease. It also provides opportunities as increasing numbers of men are diagnosed with indolent disease by screening.

• Clinical trials in men with prostate cancer of agents targeting the IGF-system are unlikely to resume unless convincing predictive markers are identified that could enable the selection of men most likely to respond.

• As IGFs are nutritionally dependent and they affect the progression of prostate cancer they provide an opportunity to monitor interventions aimed at reducing the risk for men with indolent disease. As most men will not suffer from their indolent prostate cancer any intervention will have to be safe from adverse effects. This favors nutritional/lifestyle interventions over pharmaceutical interventions. A better understanding of the nutritional determinants of IGFs will assist these studies. There are major differences in IGF-physiology between different animal species and these differences explain why IGF-levels are more responsive to nutritional changes in rodents compared to humans. These differences, however, limit the usefulness of animal models for such studies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.