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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - MEL-PLEX (Exploiting MELanoma disease comPLEXity to address European research training needs in translational cancer systems biology and cancer systems medicine)

Teaser

Summary

In the absence of personalised and optimised treatment, great numbers of cancer patients suffer from inefficient therapies. Malignant melanoma exemplifies a largely chemotherapy-resistant, highly heterogeneous and aggressive cancer. Novel treatment options for personalised, patient-tailored melanoma therapies can now be explored or developed through emerging and innovative research disciplines going beyond the current state-of-the-art, such as translational cancer systems biology and cancer systems medicine.
The MEL-PLEX programme was designed by European and international academic/clinical and private sector leaders in personalised melanoma therapy, melanoma systems biology and cancer systems medicine.
The MEL-PLEX aims were:
(i) to achieve an unmatched depth of molecular and mechanistic disease understanding: The individual research projects have made significant progress and provided substantial novel insight into melanoma disease complexity, using both experimental and mathematical approaches.
(ii) to exploit this knowledge to develop and validate predictive models for disease progression, prognosis and responsiveness to current and novel (co-)treatment options: The research projects provided considerable amounts of experimental data to feed into model development or validation. Similarly, projects initiated from the mathematical modelling perspective integrated clinical and/or experimental data and evidence to transfer in silico approaches into a practically relevant context.
(iii) to provide superior and clinically relevant tools and biomarker signatures for personalising and optimising melanoma therapy: By achieving the above objectives, the MEL-PLEX research activities approached this key aim during the second half of the project. In particular, attention was paid to ensure that validation strategies were followed. Several model prototypes and biomarker-focussed projects have been published.
MEL-PLEX addressed current needs in academia and the private sector for researchers that have been interdisciplinarily trained, can navigate confidently between clinical, academic and private sector environments, and have developed an innovative and creative mindset to progress research findings towards applications.

Work performed

MEL-PLEX research activities were grouped into two work packages (MEL-TARGET and MEL-MARK). In MEL-TARGET, novel drug candidates that activate death receptors and block pro-survival kinases or growth factor receptors were tested, associated with the parallel development of predictive systems models of cellular signalling. These approaches were combined with efforts to develop modelling strategies by which treatment responsiveness could be predicted and that in the future may have potential as innovative patient stratification and treatment decision tools.
The results reported for MEL-TARGET comprehensively described the biological, biochemical and mathematical approaches that merged within individual projects to deliver novel insights into drug action, signal transduction and response heterogeneity. From this, novel tools to understand signalling and to predict responsiveness were developed.
In MEL-MARK, research activities focused on identification and validation of innovative systems-level biomarkers for disease progression, improved prognosis and patient stratification. The processes contributing to acquired resistance to targeted therapeutics, the role of the tumour microenvironment and the contribution of â€œwhole bodyâ€ physiological parameters to treatment success were obscure and significantly limited the quality and success of melanoma management. In MEL-MARK, disease relevant pathways and associated models for disease processes were studied for their potential as novel approaches to prognosticate or predict melanomagenesis, progression, and (co-)treatment responsiveness.
Associated to this, a dedicated training programme was implemented, covering basic, transferable and specialist skills in the research domains that merge within MEL-PLEX. Eight network-wide courses were organised with a range of activities from hands-on technical workshops to interactive soft skills courses, linked also to additional dissemination and outreach activities via MEL-PLEX sponsored symposia in which international experts were hosted or round-table discussions open to lay audiences were organised. The consortiumâ€™s activities could be followed online on MEL-PLEX website and social media (Twitter and Facebook).

Final results

Novel insight into disease-relevant signalling in melanoma has been obtained by the innovative research approaches followed within MEL-PLEX. These contributed significantly to an improved understanding of disease relevant signalling, allowed to assess the potential of novel therapeutics and their targets and introduced novel concepts for systems-based patient prognosis, disease progression and treatment responsiveness. The involvement of key private sector partners in the programme assisted in identifying avenues for exploitation of results and also provided career perspectives for MEL-PLEX trainees within the European knowledge- and skills-based economy.
The impact of MEL-PLEX on the career development of ESRs was achieved through excellence in training, research and innovation, thereby establishing an internationally unique training environment in translational systems biology and cancer systems medicine, supradisciplinary fields of growing interest and with undefined limits. As part of the essential mobility and intersectoral experience, the ESRs were exposed to diverse work and cultural environments, contributing to the European identity of each ESR.
Through cutting edge research projects and technologies that brought together leading players in traditionally separated research disciplines, MEL-PLEX developed a unique training programme which allowed the ESRs to face complex challenges in contemporary and future multi-discipline research, enhancing their employability and broadening their career perspectives. It is also noteworthy that similar intersectoral training benefits were observed within the group of the participating principal investigators and their staff, reflecting that the participating organisations also benefitted.
This objective was achieved, not only by implementation of planned secondments and intersectoral interactions, but also by additional training opportunities that arose during the programme life-cycle, some of which were not forecasted in the proposal, and by complementary research interactions that branched from the original projects.
MEL-PLEX developed a highly innovative doctoral training programme in the emerging supradisciplinary fields of translational systems biology and cancer systems medicine, which can be used as a framework for development of structured doctoral training in these fields. Through the mutual recognition between academic and non-academic partners of the training delivered by the MEL-PLEX Training Committee events, the foundation on which future permanent or durable interactions extending beyond the lifetime of MEL-PLEX was laid.
The complementarities in expertise represented one of the core strengths of MEL-PLEX. During the 48 months project, MEL-PLEX partners invested considerable efforts in aligning local existing training capacities, devising novel and multi-site research training components, and offering their capacities for unforeseen training needs that arose throughout the programme.