SYS-MEL · SYSTEMS-BASED VIEW OF MELANOMA PROGRESSION: TOWARDS NOVEL DIAGNOSTIC (AND THERAPEUTIC) APPLICATIONS

SYSTEMS-BASED VIEW OF MELANOMA PROGRESSION: TOWARDS NOVEL DIAGNOSTIC (AND THERAPEUTIC) APPLICATIONS

The incidence of melanoma is increasing worldwide, with an estimated 87,110 new cases of melanoma and nearly 10,000 deaths from the disease in the USA in 2017 (American Cancer Society, 2017; www.cancer.org). These upward trends are worrying, as malignant melanoma is one of the most difficult cancers to treat, due to its ability to spread quickly and its resistance to standard chemotherapeutic agents. In order to counteract this trend, targeted therapies that inhibit melanoma metastasis are required and are being developed. Melanoma is a disease with high metastatic potential even at very early stages of development. In present clinical practice, screening for melanoma is based on clinical examination. Current methods for detection, diagnosis, prognosis, and treatment of melanoma fail to satisfactorily reduce the morbidity associated with the disease. A biomarker assay that could reduce these uncertainties would have a significant positive clinical impact. The SYS-MEL research programme investigated the molecular basis underlying melanoma which may hold the key to improving patient care. SYS-MEL was a comprehensive project in which researchers from both the academic and the industrial field worked together to identify and validate candidate melanoma biomarkers that could be useful for clinical practice. It focused on identifying novel prognostic and predictive biomarkers for melanoma, as well as new targets for melanoma treatment. The SYS-MEL project made particular use of advanced systems biology techniques to link all work projects. Core methodologies that were employed included antibody-based profiling, computer assisted pathological interpretation and sophisticated systems models linked to biological pathways. Use of tissue microarrays (TMAs) allowed hundreds of samples from melanoma patients to be assessed simultaneously. Subsequently, combination of TMA-derived data, image analysis and high-performance computing led to high-throughput validation of protein biomarkers. The results generated were utilised in systems modelling to add benefit to/improve upon classical biostatistical analysis, to better predict inherent risk of disease, progression and outcome to standard chemotherapy. All Deliverables and Milestones for the SYS-MEL project have been completed in the timeframe originally envisaged. A large collection of candidate biomarkers were evaluated in respect to expression within clinical tissues, with several of these showing strong promise in terms of prognostic and predictive utility. In WP1, at least one of several epigenetically regulated biomarkers were found to have significant prognostic ability. In WP2, a potential prognostic apoptotic biomarker panel was identified, with further validation planned to be carried out beyond the SYS-MEL project. In addition, a dynamic mathematical model of the PREX pathway was developed that establishes a traceable relationship between biochemical changes and biological outputs allowing the analysis of melanoma cell migration and invasion, and prediction of the effects of mutations on anti-cancer therapeutics. This model allowed the identification of components of specific pathways that may represent potential therapeutic opportunities in melanoma. The results from the SYS-MEL project have been published in multiple leading scientific journals including BMC Medicine, the Journal of Biological Chemistry and Oncology Research; and presented at national and international conferences, with a number of manuscripts still in preparation pending further validation of results. Work on the promising targets identified during the project will be brought to completion beyond SYS-MEL, facilitated by the relationships and collaborations established during this project with a number of potential product opportunities for the remaining industry partner. Crucially, the SYS-MEL project provided a fertile training ground for 14 early stage and experienced researchers, each of whom gained valuable inter-sectoral experience alongside increased scientific knowledge and training. The fellows finished the SYS-MEL project with a multitude of technical and transferable skills in high demand for a variety of careers in many different sectors. This is reflected in the career progression of the fellows following their positions on the SYS-MEL project. The have found employment in many different sectors including the academic, clinical, industry and the charity sectors. The SYS-MEL project (www.sysmel.com) was funded under the Marie Curie Industry-Academia Partnerships and Pathways (IAPP) programme and ran for 4 years from November 2013 – October 2017. This was a pan-European project that functioned as a collaborative effort undertaken by 7 partners (5 academic institutions and 2 industrial partners) across 5 EU countries. It had an overall budget of just over €1.9 million, which funded both recruitments and secondments between the seven partners.

Data: CORDIS, © European Union