This proposal seeks to discover a novel process for staging disease based upon the molecular characteristics of cancer stem cells. We propose to use physical techniques and inherent physical phenomena of the samples as the basis to investigate a new realm for molecular pathology and also to use these techniques as an aid to current pathology.The research is needed into the fundamental differences between the associated model cell lines to enable the elucidation of biochemical markers to aid histopathology. The techniques are very complimentary - SIMS and MIMS are mass spectral techniques and ATR-IR and Raman are spectroscopic. Utilising these techniques we will cover the full range of elemental (isotopic), molecular and macromolecular information. This will provide translational molecular markers which can be identified by more clinically routine methods e.g staining for chemicals elucidated by this study.

Radiotherapy is an important cancer treatment given to about 125,000 patients each year. It is typically delivered in daily doses (fractions) over a period of several weeks using multiple high energy X-ray (and now proton) "beams". The beams are individually shaped for each patient and designed to overlap at the precise location of the target disease. The intention is to give maximum dose to the cancer cells while minimising dose to nearby healthy tissues. Usual practice is to plan the arrangement and shape of these treatment beams based on CT images taken before treatment begins. Ensuring that the patient and their tumour target are in the correct position for treatment on each day of their therapy is challenging. Small changes (more than a few millimetres) could invalidate the pre-treatment planning leading to the target receiving too low a dose of radiation (and hence reduced chance of cure) or healthy tissues receiving too high a dose of radiation (and hence increased chance of side effects). The use of cone-beam CT (CBCT) imaging within the treatment room to check patient position, pose, and anatomy just before the radiation beams are switched on has recently become widespread. However, changes in patient shape can be complex, making it difficult to calculate whether the resulting change in radiation dose received will be significant - that is, will it be necessary to alter the pre-planned treatment to take account of the change? Our aim is to simplify this decision process. We will develop a computerised method that uses a patient's CBCT image to calculate changes from their prescribed and planned dose. Currently this is not possible because calculation of radiation dose requires accurate data on tissue density within the patient, in order to determine how X-rays (or protons) will interact with their anatomy. Unlike CT images, which are used to generate the initial treatment plan, CBCT images do not give accurate information on tissue density. This project will develop a method to "correct" the CBCT images so that the tissue density information that they contain can be used to directly compute delivered doses. This will be of significant benefit to radiotherapy patients since staff we be able to quickly check that the correct dose will be delivered, or if it is necessary to take action to avoid incorrect doses. Currently this process is very time consuming - tissue boundaries have to be manually drawn onto CBCT images and assumed density values assigned to each region. The technology we propose to develop will accelerate such assessments, estimated to be necessary for about one fifth of CBCT images. A further benefit is that our correction method not only restores accurate CBCT density values, but also markedly improves visual image quality. This makes images easier to interpret and more suitable for automatic analysis, with potential for further time savings. The project builds on our previous work, where we have developed a correction method that appears to be effective for pelvic or head and neck images. We have acquired a UK patent for this invention, ensuring that benefits and value to the NHS can be maximised. In this project we propose to extend our method for use in lung images. This site is challenging due to the large differences in tissue densities present (lung, soft-tissue, bone), and the inherent respiratory motion. We will additionally investigate the suitability of corrected CBCT images for the planning of proton radiotherapy, a looming challenge as we move towards the opening of the first high-energy proton therapy centres in the UK.

In the UK one in two people are diagnosed with cancer during their lifetimes and of those who survive 41% can attribute their cure to a treatment including radiotherapy. Proton beam therapy (PBT) is a radical new type of radiotherapy, capable of delivering a targeted tumour dose with minimal damage to the surrounding healthy tissue. The NHS is investing £250m in two new "state of the art" PBT centres in London and Manchester. In addition, Oxford has attracted £110m (from HEFCE and business partners) for its new Centre for Precision Cancer Medicine, incorporating PBT. This EPSRC Network+ proposal seeks to bring the EPS community together with clinical, consumer and industrial partners and develop a national research infrastructure and roadmap in proton therapy. It capitalises on ~£300m of government investment and affords an opportunity for those not directly involved in the new proton centres to be actively involved in the national research effort in this area. This project has the backing of NCRI Clinical and Translational Radiotherapy Working Group and NHS England and will work with the national Proton Physics Research and Implementation Group of the National Physical Laboratory. It also involves industrial stakeholders, consumer groups and international partners (including PBT centres in Europe and USA and CERN). While PBT offers patients many advantages it also presents a wealth of technical challenges and opportunities where there is an unmet research and training need. This is where there the involvement of the EPS community is vital since this challenge in Healthcare Technologies requires expertise from across the EPS spectrum and maps on to themes in ICT, Digital Economy, Engineering, Mathematics, Manufacturing the Future, and the Physical Sciences and also finds synergies within quantum technologies. It directly maps onto the cross cutting capabilities identified in the Healthcare Technologies Grand Challenges. This is a highly multi-disciplinary area at the frontiers of physical intervention, which achieves high precision treatment with minimal invasiveness. This Network+ is particularly timely; it will afford the UK the opportunity to develop a world-leading research capability to inform the national agenda, capitalising on existing research excellence and the synergies that can be developed by bringing the clinical and EPS areas together. It will also collaborate with existing doctoral training provision to train the next generation of leaders where a national need has been identified. This proposed Network+ will create a national infrastructure to meet a national research and training need and will allow the UK community to work together in the multi-disciplinary field of proton research. This proposed Network+ will create a sustainable national proton beam infrastructure by drawing together sites where proton beams are already available (albeit at lower energies) and providing a route for the research community to access these facilities. As the new proton centres come on line they will add to this national resource and the centres will work together to provide a virtual national infrastructure for the UK, which by the end of the Network+ will be fully sustainable. The Network+ will also provide a route for those interested in the field but not requiring proton experiments to become involved. In addition, the Network+ will offer secondments ("Discipline Hops") into the clinical environment in both the UK and in PBT centres overseas. Working with NHS England the Network+ will develop a PBT training scheme. This will link the existing NHS provision with EPSRC Centres for Doctoral Training and allow equivalencies to be established and so provide a "fast track" to a skilled workforce and the next generation of leaders. The Network+ will also seek to engage with industry through joint research and secondments and with consumer groups, policy makers and the general public.

A major part of the diagnosis of any disease but particularly various forms of cancer, is obtained though a biopsy. This involves removing a small sample of tissue, or a few cells, from the patient. These samples, either tissue or cells are then examined by a pathologist looking down an optical microscope. In most cases the sample is stained with a combination of dyes to help gain some contrast. In most cases, based upon visual inspection of the sample a diagnosis is made. This process if far from ideal since it relies on the expertise of the clinician concerned as is subject to intra in inter observer error. Recently a number of proof of concept studies have shown that molecular spectroscopic techniques such as infrared and Raman are capable of distinguishing diseased from non diseased cells and tissue based upon the inherent chemistry contained within the cells. The UK is at the forefront of these developments but there are many hurdles that need to be overcome if this technology is to move from the proof of concept stage through the translational stage and into the clinical setting. It is the belief of the academic community that we are much more likely to overcome these hurdles if we pool our resources, bring in both industrial and clinical partners and work on these generic problems together. This application is for funding to support such a network of partners for the next three years.

The UK is presently contracting to supply two centres where the NHS will carry out treatment of many cancers with protons. Whilst the current generation of X-ray linacs can deliver excellent treatment using the technique known as intensity-modulated radiotherapy (IMRT), there is nevertheless a small dose inherently deposited in tissues outside of the intended tumour treatment site. For certain hard-to-treat tumours near to critical organs, and in particular when treating some childhood cancers, it would be beneficial to avoid this so-called out-of-field dose. Proton therapy can do this because protons interact in tissue quite differently to X-rays; there is a much more pronounced peak in the delivered dose which can be varied in depth to target the tumour accurately. The two new centres at Christie Hospital and UCLH in London can treat at any depth as they will use high-energy accelerators, augmenting the present low-energy proton centre at Clatterbridge which is restricted to shallow eye treatments. But there's a problem. Whilst the proton dose is deposited at a specific depth, it can be hard to set the proper energy to reach that depth. This is because current-generation imaging such as X-ray computed tomography doesn't do a good enough job at allowing clinicians to estimate the amount the protons will slow down on their way to the tumour. One promising way around this is to do imaging with protons as well: no conversion from X-ray measurements is needed, but proton imaging needs more energetic protons that can pass right through the patient where their residual energy is measured to work out how much was lost on the way. Suitable high-resolution detectors for this are under development in the UK, but as yet there is no suitable source of the protons themselves. This is where our linac comes into the story. Recent research at our institute and elsewhere means that we think we can build a linear accelerator (linac) that can boost the protons from the energy available at present adult treatment centres such as Christie up to the energies required for imaging. To retrofit to existing treatment centres requires such a linac to be small, and hence that energy gain must occur in a very short distance; this is the hard part, and requires the use of high-frequency ('X band') accelerating cavities previously developed for use in particle physics experiments. We hope in this project to demonstrate the first truly high-gradient proton linac for imaging, taking the knowledge previously developed for physics research. Our aim in developing a high-gradient linac is that it can be used to provide improved imaging for patients in the UK and abroad. It is thought that improved imaging using protons could reduce the required margins during tumour treatment by as much as 5mm, sparing surrounding sensitive tissues and thereby reducing side-effects and improving long-term outcomes for patients. Later on, we think the same linac technology could also be used to provide protons directly for treatment, where the use of a linac can allow finer control of the treatment depth. Also, if the accelerating structures can be made small enough, they could even themselves be fitted onto the gantry that rotates the proton beam around the patient, meaning that smaller, cheaper treatment facilities become possible. These single-room centres are seen as one way to increase the access to proton therapy for patients. We hope our project and the advantages it brings will in the future widen the range of cancers for which proton therapy is beneficial.