Our research aims to understand the contribution of insulin-like growth factors (IGFs) to cancer biology and use this information to benefit patients with cancer.
People with congenital IGF-1 deficiency are strongly protected from developing cancer, while those with high blood IGF-1 levels are at increased cancer risk. These are almost certainly causative associations. IGFs binds to cell surface IGF receptors (IGF-1Rs), promoting cancer cell growth, spread, and therapy resistance. Therefore, blocking IGF actions could suppress cancer development and increase sensitivity to anti-cancer treatments. However, trials of IGF-1R inhibitors have failed, largely due to lack of predictive biomarkers to identify those patients who do respond. This suggests we need better understanding of IGF biology to exploit this target.
Our previous work focused on three main areas. First, we showed that IGF-1Rs are up-regulated in prostate and renal cancers, and detectable in advanced primary tumours and metastatic disease. Secondly, we reported that IGF-1Rs translocate from the cell surface to the nucleus of human tumour cells, undergoing recruitment to regulatory regions of genes that promote cancer cell survival and motility (see Figure 1). Nuclear IGF-1R associates with adverse prognosis in renal cancer and advanced stage in prostate cancer, suggesting a link with aggressive tumour behaviour. Thirdly, our data support a role for IGFs in the DNA damage response: IGF-1R expression associates with adverse outcome after radiotherapy for prostate cancer, and inhibiting IGF-1R delays repair of radiation-induced DNA double-strand breaks (see Figure 2A-C). These findings promoted us to investigate the response to endogenous DNA damage, leading us to identify a critical role for the IGF axis in regulating DNA replication. We show that IGF blockade induces replication stress (Figure 2D-F), a phenotype with potential for exploitation via identification of predictive biomarkers and rational combination therapies.
Currently, we are exploring whether these newly identified roles for IGFs influence the risk of developing cancer. With Cancer Research UK support we are investigating differences between cancers that arise in low vs high IGF environments. Reciprocally, with support from Prostate Cancer UK, we are testing effects of IGF inhibition in prostate cancer, including preclinical models and a clinical trial due to open mid-2021, aiming to identify critical mediators of IGF actions that promote cancer progression. The long-term aims are to assess the potential of IGF inhibition as a route to prevent or delay progression of early cancers, and to identify novel targets for risk reduction.
Figure 2: IGFs regulate the cellular response to exogenous and endogenous DNA damage. A. In men treated with radical radiotherapy (RT) for prostate cancer, high IGF-1R associates with risk of recurrence. B, C. IGF-1R inhibition (IGF-1Ri): B, enhances radio sensitivity of human prostate cancer cells; C, delays resolution of radiation-induced DNA damage marked by yH2AX foci. D. We identify a novel role for IGF-1 in regulating expression of the RRM2 subunit of ribonucleotide reductase (RNR) to influence dNTP supply. E. IGF-1R depletion down regulates RRM2 and delays progression of the replication fork in DNA fibre assays. F. IGF inhibited G1 (cyclin A negative) cells accumulate 53BP1 bodies to protect incompletely-replicated DNA from erosion. The changes shown in E, F indicate a phenotype of replication stress, which presents opportunities for therapeutic exploitation.