Targeting the Insulin-Like Growth Factor (IGF) System Is Not as Simple as Just Targeting the Type 1 IGF Receptor

Increased signaling of the insulin-like growth factor (IGF) system via alterations in expression levels of its components has been demonstrated in various tumor types. Numerous experimental studies have supported the involvement of the IGF system signaling axis in tumor initiation and progression. These studies, combined with data that link alterations in the levels of circulating IGFs with cancer risk and prognosis, have focused on the IGF-1 receptor (IGF-1R) as a therapeutic target for patients with cancer. As a consequence, most therapeutic strategies have been designed to specifically inhibit IGF-1R but have for the most part ignored the insulin receptor (IR), based on concerns that targeting IR would lead to unacceptable toxicity both because of its role in physiologic metabolism and because we frequently try to oversimplify biologic complexity whenever we are urged to find practical, friendly solutions for clinical practice. Although this is an understandable and necessary starting point in the complex and long-lasting processes that leads to translational biology, the crude reality of the results obtained from phase I and II studies suggest a need for researchers to be humble and go back to the drawing board. Cancer research has substantially neglected the role of IR, and it remains unclear whether and to what extent avoiding the inhibition of IR has compromised the efficacy of anti-IGF-1R therapy. Clarifying its role might also help us take advantage of older drugs that could offer new perspectives in cancer care.