We are studying the role of insulin-like growth factor (IGF) signalling in tumour biology, aiming to use this information to develop new ways to prevent and treat cancer.
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.
Dr Macaulay is also contributing to the clinical evaluation of IGF inhibitory drugs, and the establishment of a Preclinical Validation hub that is embedded within the Oxford Cancer Research Centre. The aim is to provide preclinical support and optimisation for clinical trial proposals, including the evaluation of targeted drugs in new indications and/or novel combinations.
Figure 1: IGF-1R undergoes nuclear translocation. Left: prostate cancer cells show IGF-induced change in IGF-1R localization from membrane-associated to punctate nuclear signal upon IGF treatment. Centre: three clear cell renal cancers showing different patterns of IGF-1R staining: upper, predominantly membrane; centre, cytoplasmic; lower, nuclear. Right: nuclear IGF-1R is associated with adverse survival in patients.
Figure 2: IGF-1R inhibition delays repair of DNA double strand breaks. Irradiated prostate cancer cells stained for yH2AX as a DSB marker. DNA damage is repaired within 24 hr in control cells but not in IGF-1R inhibited cells, indicating persistence of toxic damage.
Dr Valentine Macaulay is Associate Professor and Honorary Consultant in Medical Oncology in the Department of Oncology, University of Oxford. Her clinical interests are in melanoma and prostate cancer, and in testing the potential of novel signalling inhibitors to enhance sensitivity to conventional anti-cancer treatments. She qualified as a doctor at Charing Cross Hospital Medical School and trained in Medical Oncology at the Royal Marsden Hospital London and Churchill Hospital Oxford. Following a PhD with Alan Ashworth at Chester Beatty Laboratories in London, her postdoctoral training was supported by MRC Clinician Scientist and Cancer Research UK Senior Clinical Fellowships.
Macaulay VM, Middleton MR, Eckhardt SG, Rudin CA, Juergens RA, Gedrich R, Gogov S, McCarthy S, Poondru S, Stephens A, Gadgeel SM. Phase I dose escalation study of linsitinib (OSI-906) and erlotinib in patients with advanced solid tumors. Clinical Cancer Research, in press.
Ramcharan R, Aleksic T, Kamdoum WP, Gao S, Pfister SX, Tanner J, Bridges E, Asher R, Watson AJ, Margison GP, Woodcock M, Repapi E, Li J-L, Middleton MR, Macaulay VM. IGF-1R inhibition induces schedule-dependent sensitization of melanoma to temozolomide. Oncotarget, epub 15 Oct.
Dale OT, Aleksic T, Shah KA, Han C, Mehanna H, Rapozo DC, Sheard JD, Goodyear P, Upile NS, Robinson M, Jones TM, Winter S, Macaulay VM. IGF-1R expression is associated with HPV-negative status and adverse survival in head and neck squamous cell cancer. Carcinogenesis 36: 648-55, 2015.
Lodhia KA, Gao S, Aleksic T, Esashi F, Macaulay VM. Suppression of homologous recombination sensitizes human tumor cells to IGF-1R inhibition. Int J Cancer 136:2961-6, 2015.
Gao S, Bajrami I, Verrill C, Kigozi A, Ouaret D, Aleksic T, Asher R, Han C, Allen P, Bailey D, Feller S, Kashima T, Athanasou N, Blay JY, Schmitz S, Machiels JP, Upile N, Jones TM, Thalmann G, Ashraf SQ, Wilding JL, Bodmer WF, Middleton MR, Ashworth A, Lord CJ, Macaulay VM. Dsh homolog DVL3 mediates resistance to IGF1R inhibition by regulating IGF-RAS signaling. Cancer Res. 2014 74:5866-77.
Chitnis MC, Lodhia KA, Aleksic T, Gao S, Protheroe AS, Macaulay VM. IGF-1R inhibition enhances radiosensitivity and delays double-strand break repair by both non-homologous end-joining and homologous recombination. Oncogene 2014, 33: 5262-5273.
Aleksic T, Chitnis MM, Perestenko OV, Gao S, Thomas PH, Turner GD, Protheroe A, Howarth M, Macaulay VM. Type I IGF receptor translocates to the nucleus of human tumor cells. Cancer Res 2010 70: 6412-9.
Nick Coupe, Clinical Research Training Fellow
Lina Guo, DPhil Student
Victoria Ma, DPhil Student
Eliot Osher, Postdoctoral Researcher
Wilfride Petnga Kamdoum, DPhil student
Guillaume Rieunier, Postdoctoral Researcher
Chris Towers, Postdoctoral Researcher
Frances Willenbrock, Postdoctoral Researcher
Xiaoning Wu, MRes Student