Manchester Academic Health Science Centre Technology Hub: Clinical Proteomics Centre for Stratified Medicine

The genomic and post-genomic age promises much for clinical medicine, as we can now sequence genomes (the blueprint), and measure gene expression fairly routinely and now we can measure the amounts of proteins (the structural and catalytic functional entities in the cell) produced. Yet, to date, the biomedical community have struggled to integrate these technologies and generate the impact anticipated some years ago. The University of Manchester proposes to engage with this challenge by setting up a completely new facility, building on its strengths in biochemistry, to enable clinicians to choose the right treatment for the right patient at the right time. The biochemistry base that will be built, using state of the art technologies, can serve this objective in a number of different ways for a wide range of different diseases. Furthermore, the benefits generated from the facility will be available to researchers from other universities and industrial partners (such as drug companies) to use, with the aim to maximise its impact in diagnostic and translational medicine beyond Manchester.

This new facility will use a new development of mass spectrometry that supports the measurement of many proteins within a sample (such as blood, urine, or from tissue such as a tumour biopsy) within a much shorter time than has ever been possible before. Such techniques will be of huge benefit to clinical researchers as it will allow them to see the differences between samples from, for example, healthy people and people with a specific disease - this will give insights into how that disease develops and, importantly, how it might be treated. In addition, by examining the differences in the levels of particular marker proteins from patients who respond to a drug compared to those who don't respond, doctors will be able to identify which drug is the best treatment for individual patients. This will have economic benefit as drugs will not be used on patients who will receive no benefit from them. We will look in the first instance for such protein markers through the disease course, and treatment response in rheumatoid arthritis, psoriasis and cancer.

This bid proposes the development of a unique world-leading clinical proteomics centre (CPC) for stratified medicine and mechanistic studies of disease. The objectives for the proposed centre include the pragmatic discovery of novel protein biomarkers to lead to early diagnosis of disease, stratification of patients according to their disease endotype and also according to their therapeutic response to a specific treatment. Additionally, we anticipate the CPC will offer a valuable resource for experimental medicine studies to understand the basis of disease mechanisms. Within the proposed CPC we will apply the very latest in innovative mass spectrometry-based technology on a high capacity throughput, for the first time in the UK. Sequential Window Acquisition of all THeoretical fragment-ion spectra Mass Spectrometry (SWATH MS), combined with Selected Reaction Monitoring (SRM) proteomics techniques will allow the creation of a digitised, quantitative, permanent record of the proteome. Linkage of proteomic data to electronic health records through the Farr@HeRC health informatics centre will be achieved through a secure 'eLab' platform, allowing the integration of complex molecular phenotyping with endotypic data (such as therapeutic outcome and medical history). Exemplar stratified medicine projects will be enabled once CPC is set up, and will include the use of samples from the MRC-funded stratified medicine programmes around psoriasis (PSORT) and rheumatoid arthritis (MATURA), where the digitised proteome can be interrogated alongside other 'omics and clinical data. Additionally, a number of other mechanistic studies around leukaemia and other solid cancers have already been identified and will proceed when the CPC is established. Combined with validation and verification platforms, the facility will offer unparalleled power to discover novel biomarkers and elucidate the underlying pathophysiological mechanisms of disease.

1) Who will benefit from this research?

- Clinical scientists and experimental medicine researchers
- Clinicians, NHS
- Patients
- Drug discovery/ development groups
- Industry, including big pharma and biotech

2) How will the above groups benefit?

In short, the groups listed above will benefit from a quicker time to clinical validation of biomarkers and the improved prospect of personalised medicine penetration into the clinic with associated economic benefit.

Specifically-
- Clinical scientists and experimental medicine researchers will benefit through being able to access an innovative high capacity resource not currently available elsewhere in the UK, allowing them to undertake discovery biomarker projects and experimental studies in a fraction of the time. The ability to create a permanent digitised record (and subsequently iteratively mine this) will allow precious clinical samples and biobanks to be used sparingly;
- Clinicians and the NHS will benefit through the ultimate development of improved diagnostics and predictors of response, allowing earlier diagnosis and reduction in prescribing errors - all of which will ultimately reduce the necessity of inappropriate or aggressive treatment and, in turn, the economic burden of disease on the health service;
- Patients will benefit through better diagnostics and 'theranostics' by being detected earlier (improving outcome) and, following diagnosis, by being treated right first time;
- Drug discovery and development groups will be able to identify those individuals who are most likely to benefit from the drugs they are developing and allowing them to be targeted appropriately (reducing side effects and non-response);
- Pharma will benefit by being able to access a facility which will allow them to identify novel "druggable" targets through the comparison of proteomic signatures from patients and healthy volunteers, mass spectrometry instrument manufacturers (and specifically AB SCIEX and Waters) will benefit through having their techniques validated and translated into clinical practice (and the potentially larger market share this will bring), smaller biotech will benefit from pharma's increased use of protein or expression based diagnostics and the opportunities this will bring in terms of companion diagnostic development