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MELanoma GENetics - understanding and biomarking the genetic and immunological determinants of melanoma survival

Periodic Reporting for period 2 - MELGEN (MELanoma GENetics - understanding and biomarking the genetic and immunological determinants of melanoma survival)

Reporting period: 2017-06-01 to 2019-12-31

The MELGEN Early Training Network (ETN) and Consortium was designed as an environment for long-term, collaborative, cancer genetics research with the ultimate aim of improving precision (personalised) medicine. MELGEN has worked primarily to understand survival from melanoma skin cancer and response to therapies using a variety of cutting-edge scientific techniques with a focus on genetics and immunity. A smaller complementary proportion of the work of the consortium was designed to identify previously unrecognised inherited genes which when mutated cause families to be at increased risk of melanoma.
MELGEN’s work on tumours is focused on determining which genes are mutated (changed) or “expressed” differently in melanomas removed from patients who survived and those who did not. The genetic make-up of a cancer largely determines how the cancer cells behave and finding the genes which are altered tells us something important about that behaviour and what can be done to modify how the cell behaves leading to better hope of cure. By combining approaches MELGEN has led to better understanding of the biology of melanoma allowing researchers to explore potential new treatment options. The tumour work has increased understanding of the key role that immune responses to melanoma are strong determinants of outcome and response to therapy, and progress was made in measuring responses which it is hoped will develop over time into clinically useful biomarkers. An important role for vitamin D/vitamin D receptor signalling in melanoma progression was established and the harmful effect of smoking in terms of melanoma survival.
In order to improve the survival of melanoma patients with advanced disease we have to learn how better to select therapies for patients. A key MELGEN aim was to identify characteristics of the patient and his/her cancer which predict response to a drug. This is often called personalized medicine, and tests which allow medical teams to advise the patient about what treatment is likely to be best for them are called predictive biomarkers. Groups in Leeds, Zurich and Essen are working towards the discovery of such predictive biomarkers and high impact papers were published from Essen and Zurich in this field giving insights into how immune responses to melanoma develop giving rise to hopes of tests to allow personalized medicine.
A key aim was to ensure that MELGEN maximises the collaborative environment between centres, commercial partners and the ESRs. Network-wide scientific training events, together with complementary skills workshops and scientific meetings at which all students were encouraged to present to a wider scientific audience, have helped to forge strong bonds of scientific collaboration and friendship between the ESRs. The host laboratories were very encouraged by this interaction and were convinced of the merits of training within a Marie-Curie consortium.
Local and international outreach/engagement was actively encouraged with the ESRs contributing regular blog articles to the MELGEN website, visiting schools and public/patient events to talk about their work in MELGEN as well as the wider health implications of sun safety. The ESRs received training on establishing a digital presence which resulted in dissemination of their own scientific results within the scientific community and beyond, and broadened their own awareness of evolving science.
Key research includes:
a) ESRs in Cambridge, Leiden and Oslo have worked on finding inherited melanoma susceptibility genes. Extensive exploration of genetic data generated from the blood of individuals in families at increased risk of melanoma identified some interesting new candidates for genes predisposing to melanoma. Oslo and Leiden went on the explore and publish the biological impact of mutations in some of these genes and the Oslo group used novel approaches to doing so, by growing pluripotential cells in the laboratory derived from samples of skin given by patients in Leeds.
b) ESRs in Leeds and Lund used data on how genes are expressed in melanoma tumours to identify groups of tumours with signs of different immune responses which also show differences in survival. These ESRs benefit from the opportunity to validate their findings in the other’s data. They used different computer (bioinformatic) methods to develop “true” biomarkers. i.e. tests which will perform well in melanoma patients treated in different countries. The Leeds group published important papers reporting use of gene expression to identify different subtypes of melanomas with differing immune responses to the tumour and showed that smoking seriously impacts on survival for some particular subtypes. The gene expression data were also used to show that vitamin D levels and the biological pathways downstream of vitamin D play a significant role in controlling the growth of melanoma cells and promoting immune responses to melanoma. This provides more evidence that avoiding vitamin D deficiency is important for melanoma patients. An ESR in Essen is studying genetic changes in the Interferon-gamma pathway genes that she has found to have a significant negative impact on melanoma patient survival.
c) Zurich identified two potential biomarkers which could predict disease progression in patients under treatment using check-point inhibitor therapies. Both of which were published during the grant period.
The MELGEN groups very much appreciated Marie-Curie funding: it resulted in key developments within each consortium member group. Longer term collaborations were established, and many of the students have already moved on the grow in science. Others will follow. MELGEN groups strongly recommend this approach to training.
MELGEN provided early stage researchers (ESRs) with the necessary skills to enable European research institutes and Biotech companies to compete internationally, and enhance the ESRs’ career opportunities, by:
• Giving access to forefront genomics;
• Delivering quality statistics and bioinformatics training;
• Promoting access to science processes in the commercial sector;
• Carrying out topical research related to immunotherapies and biomarker discovery;
• Fostering cross-fertilisation of research between units in different countries.
MELGEN benefitted the commercial companies, especially with respect to the development of clinical biomarkers, by providing them with academic and clinical partners, as well as providing a pool of outstanding graduates at the end of their training.
The researchers benefitted from tailored research and complementary training, providing a diverse skill set which has already raised their scientific profile in research workshops, online dissemination and private sector placements. Through being exposed to a highly supportive group of researchers who have achieved success through collaboration the ESRs understand how a culture of long-term collaboration is crucial to progress and success. Many of the ESRs are already developing into independent researchers with the potential to lead future training and research networks.
MELGEN’s commercial partners played a vital role in the network’s management, training and research activities. Via placements, technical skills were transferred between laboratories, and the different methodologies employed by those laboratories harmonised, increasing the international competitiveness of participating companies and institutions.
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