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Development of ecosystems for precision medicine

DNA

The genomic and post-genomic age promises much for clinical medicine, largely because we can now comprehensively sequence genomic DNA to identify polymorphisms, patterns and mutations. We can also measure gene expression routinely and systematically and with high sensitivity measure the amounts of proteins produced.

In the arena where we can successfully and cheaply sequence a genome, measure proteins and RNA systematically, the challenges around effective “big biodata” analysis moving to treatment or prevention strategies remain.

Developments made also need to be integrated into the regulatory frameworks for provision of healthcare and implementation of new treatment strategies. Novel tests and approaches need to be validated and meet the compliance requirements of regulatory bodies such as the Food and Drug Administration (FDA) and the Medicines and Healthcare products Regulatory Authority (MHRA). The integration of new treatment strategies and development of novel drugs needs to occur in tandem with development of regulatory compliant companion diagnostics and theranostics so that changes in clinical practice can occur as swiftly as possible.

The major targets for drugs are proteins – often the object of measurement for prognosis, diagnosis or theranostic purposes. Thus rapid and effective development of protein measurement that meet regulatory compliance requirements are key in developing new treatment strategies and the adoption of novel clinical pathways for patients.

We have developed a clinical proteomics centre for precision medicine and mechanistic studies of disease. The centre combines proteomic and genomic studies and has an associated molecular pathology innovation centre. The objectives for this venture include the pragmatic discovery of novel protein biomarkers to lead to early diagnosis of disease, stratification of patients according to their disease endotype and according to their therapeutic response to a specific treatment.

Additionally, we can use the research platform for experimental medicine studies to understand the basis of disease mechanisms. Proteomics using mass spectrometry and other approaches can be combined with genomics and patient records to more rapidly advance patient stratification and implementation of new clinical pathways. So, for example, we have used proteomics and transcriptomics to identify a novel approach to extinguish the stem cells at the heart of Chronic Myeloid Leukaemia (see Nature).

We have applied the innovative mass spectrometry-based technology in a high capacity throughput basis. Sequential Window Acquisition of all Theoretical fragment-ion spectra Mass Spectrometry (SWATH MS), combined with Selected Reaction Monitoring (SRM) proteomics techniques to create digitised, quantitative, permanent record of the proteome enabling biomarker discovery, for example as markers of risk in ovarian cancer.

Due to its high throughput capability, SWATH can be used to interrogate many samples from large biobanks/programmes. Linkage of proteomic data to electronic health records is achieved through a secure ‘electronic Lab’ platform, allowing the integration of complex molecular phenotyping with endotypic data (such as therapeutic outcome and medical history). Further stratified medicine projects being undertaken include the use of samples from precision/stratified medicine programmes in 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 solid tumour cancers are being undertaken beyond CML.

Combining validation and verification platforms with informatics power to discover novel biomarkers and elucidate the underlying pathophysiological mechanisms of disease is essential for compliance and development of new treatments. The aim of the development of new platforms for biomarker discovery and validation is to enable transformation in clinical practice within the regulatory frameworks. These new facilities and approaches enable rapid translational research for clinical purpose.

Tony Whetton


Anthony Whetton
is the Director of the Stoller Biomarker Discovery Centre and of the Manchester Precision Medicine Institute, UK. He is speaking at the Mass Spectrometry and Proteomics Congress.

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