Nuclear IGF-1R as a potential target for precision cancer medicine

The main aim of our research is to understand the contribution of insulin-like growth factor (IGF) signalling to cancer biology, and to exploit this information in the management of patients with cancer. Production of IGF-1 from the liver is regulated by growth hormone, and people with congenital deficiencies of growth hormone or IGF-1 are strongly protected from developing cancer. Conversely, people with high blood levels of IGF-1 are at increased risk of developing cancer. IGFs binds to type 1 IGF receptors that are expressed on the cell surface, promoting cancer cell growth and spread, and resistance to killing by cancer drugs and radiotherapy. Therefore, blocking the action of IGFs offers the potential to suppress cancer development, and increase sensitivity to anti-cancer treatments.
We have shown that IGF receptors are up-regulated in prostate and renal cancers, and detectable in advanced primary tumours and metastatic disease. We also demonstrated that IGF receptors undergo IGF-dependent import into the nucleus of human tumour cells, and nuclear IGF receptor is associated with adverse prognosis in renal cancer. These findings suggest a link with aggressive tumour behaviour, and we are currently investigating the role of IGF receptor in the nucleus
Our other major interest is to develop approaches to exploit IGF receptor and related signalling molecules as targets for cancer treatment. Our research aims to identify factors that influence sensitivity to drugs that block IGF receptor, and test IGF inhibition as a route to sensitise cancers to other forms of treatment. We recently showed that IGF receptor inhibition delays the repair of DNA double-strand breaks, apparently independent of its well-known ability to regulate apoptosis induction. Understanding the basis of this effect may enable effective exploitation of this approach in the clinic.