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Nominating Supervisor: Dr Valentine Macaulay

Second Supervisor: Professor Clare Verrill

The Project

The focus of this research project is the investigation of insulin-like growth factors (IGFs) as risk factors for development of cancer. In current work we are studying effects of varying IGF supply on benign and malignant prostate epithelial cells, and have made two observations that could be relevant to pro-tumorigenic effects of IGF-1. Firstly, we find that serum IGF-1 associates with altered expression of the IGF receptor (IGF-1R) in malignant prostatic epithelium. Secondly, we recently identified changes in expression of immune molecules by prostate cancer cells, which could potentially affect T cell recognition. Therefore, this project will investigate the hypothesis that a high IGF environment drives pro-tumorigenic changes in tumour epithelium, while influencing the ability to mount an anti-tumour immune response. The student will use in vitro and in vivo models and clinical data to investigate the relationship between IGF supply and immune cell function. There will also be the opportunity to analyse tissues obtained from patients recruited to an academic-led windows trial in men with early prostate cancer prior to radical prostatectomy, using multiplexed tissue markers to assess effects of IGF blockade. The student will be supervised by Dr Macaulay and her group, with second supervision from Professor Clare Verrill to provide expertise in tissue analysis and digital pathology. Thus, this project will be a collaboration between the Department of Oncology and the Nuffield Department of Surgical Sciences. This is an exciting opportunity for training in basic and translational research to understand how effects on the tumour microenvironment contribute to the association of IGF-1 with cancer risk and progression. The long-term aims of this research are to identify mediators of high IGF-1, in order to develop novel approaches to cancer risk reduction.

The Training

This project will provide training in a wide range of cell and molecular biology techniques, assays of immune cell function, microscopy, immunofluorescence, immunohistochemistry, in situ hybridisation and digital pathology. Depending on the direction of the project there may also be opportunities for training in analysis of large public datasets, fresh tissue explant culture, genome editing, proteomic and transcriptional profiling.

Publications

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. 78: 3497-3509, 2018.

Travis RC, Appleby PN, Martin RM….. Key TJ, Allen NE. A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk. Cancer Res, 2016. 76: 2288-300.

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