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 aim of our research is to understand the contribution of insulin-like growth factor (IGF) signalling to cancer biology, and 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 (IGF-1Rs) that are expressed on the cell surface, promoting cancer cell growth and spread, and resistance to killing by cancer drugs and radiotherapy. Therefore, blocking IGF actions offers the potential to suppress cancer development, and increase sensitivity to anti-cancer treatments.
We have shown that IGF-1Rs are up-regulated in prostate and renal cancers, and detectable in advanced primary tumours and metastatic disease. We also demonstrated that IGF-1R undergoes IGF-dependent import into the nucleus of human tumour cells. Nuclear IGF-1R associates with adverse prognosis in renal cancer and advanced stage in prostate cancer, suggesting a link with aggressive tumour behaviour. Supporting this concept, our ChIP-seq data reveal ligand-dependent recruitment of nuclear IGF-1R to regulatory regions of genes that promote cancer cell survival and motility.
The two main aims of current work are to investigate the function of nuclear IGF-1R, and develop approaches to exploit the IGF axis as a target for therapy. We aim to identify factors that influence sensitivity to drugs that block the IGFs, and test IGF inhibition as a route to sensitise cancers to radiation and other forms of cancer treatment. We find that IGF-1R expression associates with adverse outcome after radiotherapy for prostate cancer, and IGF-1R inhibition delays 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.
Figure 1: Nuclear IGF-1R binds regulatory regions of DNA, promoting expression of genes that drive tumour cell survival and migration. A. Membrane and nuclear IGF-1R in human prostate cancer cells. B. ChIP-seq-identifies limited number of IGF-1R binding sites that cluster near transcription start sites. C. IGF-1R binding sites (red bars) within JUN and FAM21A promoters, coincident with RNAPol2 and H3K4me1 peaks. Graphs below: ChIP-qPCR confirms IGF-dependent IGF-1R recruitment to JUN and FAM21A promoters. D. IGF-1R is detectable on JUN and FAM21A promoters in fresh samples of prostate cancer that contain nuclear IGF-1R. E. Nuclear IGF-1R binds to DNA and interacts with transcriptional regulators including RNAPol2 and GATA2, inducing expression of genes that promote tumour cell survival and migration.
Figure 2: IGF-1R as a mediator of radioresistance. A-C. IGF-1R inhibition (IGF-1Ri): A, blocks IGF-induced IGF-1R activation; B, enhances radiosensitivity of human prostate cancer cells; C, delays resolution of radiation-induced DNA damage marked here by gH2AX foci. D. In men treated with radical radiotherapy for prostate cancer (n=136), high total IGF-1R associates with risk of total and metastatic recurrence, and internalised (nuclear plus cytoplasmic) IGF-1R with biochemical recurrence. The latter category includes men experiencing recurrence within the radiation field, indicating clinical radioresistance.
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 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.
Aleksic T, Gray NE, Wu X, Rieunier G, Osher E, Mills J, Verrill C, Bryant RJ, Han C, Hutchinson K, Lambert A, Kumar R, Hamdy FC, Weyer-Czernilofsky U, Sanderson M, Bogenrieder T, Taylor S, Macaulay VM. Nuclear IGF-1R interacts with regulatory regions of chromatin to promote RNA polymerase II recruitment and gene expression associated with advanced tumor stage. Cancer Res. 2018 78: 3497-3509, epub May 7.
Earwaker P, Anderson C, Willenbrock F, Harris AL, Protheroe AS, Macaulay VM. RAPTOR unpregulation contributes to resistance of renal cancer cells to PI3K-mTOR inhibition. PLoS One. 2018 Feb 1;13(2):e0191890.
Aleksic T, Verrill C, Bryant RJ, Han C, Worrall AR, Brureau L, Larré S, Higgins GS, Fazal F, Sabbagh A, Haider S, Buffa FM, Cole D, Macaulay VM. IGF-1R associates with adverse outcomes after radical radiotherapy for prostate cancer. Br J Cancer. 117:1600-6, 2017.
Simpson A, Petnga W, Macaulay VM, Weyer-Czernilofsky U, Bogenrieder, T. Insulin-like growth factor (IGF) pathway targeting in cancer: Role of the IGF axis and opportunities for future combination studies. Target Oncol. 12: 571-97, 2017.
Aleksic T, Browning L, Woodward M, Phillips R, Page S, Henderson S, Athanasou N, Ansorge O, Whitwell D, Pratap S, Hassan AB, Middleton MR, Macaulay VM. Durable response of spinal chordoma to combined inhibition of IGF-1R and EGFR. Front Oncol. 6: 98-103, 2016
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. Clin Cancer Res 22: 2897-907, 2016.
Aleksic T, Worrall RW, Verrill C, Turley H, Campo L, Macaulay VM. Improved immunohistochemical detection of type 1 insulin-like growth factor receptor in human tumors. Immunochem Immunopathol 2:114. doi: 10.4172/2469-9756.1000114
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 human melanoma to temozolomide. Oncotarget 6: 39877-90, 2015.
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.