Drug-resistance is a major obstacle for the effective treatment of patients with high grade metastatic cancer. Currently, there is no satisfactory way to identify patients that will respond and those that will fail standard-of-care therapy. Positron emission tomography (PET) imaging offers a potential solution to this clinical problem through the non-invasive assessment of molecular processes that underpin drug-resistance. Using a multidisciplinary approach, we are developing pioneering new PET imaging agents to identify drug-resistant tumours [1-3]. Early detection of drug resistance will enable the selection of alternative therapies, thereby improving outcomes in this disease. The chick CAM A considerable limitation of current preclinical models of cancer drug resistance is the inability to recapitulate the complexity of the tumour microenvironment. Mouse models of cancer have shown wide-spread utility and adoption for both drug and imaging agent development. However, mouse models are expensive, have high maintenance and husbandry costs, and are subject to ethical issues surrounding animal welfare. Here, we will develop the chick chorioallantoic membrane (CAM) as an alternative, high-throughput method for the development of novel cancer imaging agents. The CAM is a highly vascularised extra-embryonic membrane of the chick embryo. The CAM can be accessed easily with minimal invasion to the embryo, enabling the growth of cultured cancer cell and patient-derived xenografts, complete with a co-opted vascular system [4]. The chick CAM is a well-established model for the assessment of anti-cancer drug efficacy. It has also been adapted to quantify tumour metabolism in a glioblastoma xenograft with PET [5]. This experimental model will therefore enable high throughput screening of novel radiotracers in a way analogous to standard mouse xenograft work but at the fraction of the time and cost. Using the chick CAM as a vehicle for in vivo tumour growth and vascularisation, we will develop an entirely new model for the assessment of cancer therapies and novel radiotracers: the ‘isolated perfused tumour’. The perfused tumour will have the biological complexity of in vivo mouse models of cancer, with the versatility, control and reproducibility of in vitro culture experiments. Based on the Langendorff isolated perfused rat heart, with which we have extensive experience [6-8], the chick CAM tumour will be excised and perfused through the large feeding ¬¬vessels to allow precise control over the delivery of oxygen, energy substrates and drugs in an intact tumour for the very first time. To exploit the power of the isolated perfused tissue apparatus that we have developed, we have constructed a triple-detector system around our perfusion rig which allows us to evaluate radiotracer selectivity, sensitivity and pharmacokinetics in the isolated perfused tumour. We have a parallel perfusion setup which works within a 9.4T NMR magnet which allows us to perform parallel spectroscopy experiments to assess tissue viability and metabolism [7]. Together, the chick CAM, the isolated perfused tumour and our assorted biophysical technologies will allow the evaluation of the complex tumour microenvironment with unprecedented precision using novel radiotracers developed to image tumour response and resistance to therapy. This project will train a biological scientist in the skills that they need for a career in the imaging sciences and instil in them the mindset required to be able to design and carryout careful biological characterisation of innovative cancer models. This project will expose the student to a large interdisciplinary team of academics, from whom they will acquire the surgical skills, animal husbandry and handling, biological assay development and histology skills. In addition, the student will be embedded in a Department and a Group where they will learn concepts in radiotracer design and evaluation, radionuclide imaging using PET and SPECT, data acquisition and pharmacokinetic modelling, nuclear magnetic resonance imaging, and metabolomics. As such, we intend to educate and train a uniquely skilled and versatile imaging scientist that will be highly employable on completion of their PhD.