Read more information about the melanoma research team
Professor Richard Marais receiving the Outstanding Research award by the Society for Melanoma Research in Brisbane, October 2017.
We have made huge progress in the treatment of patients with advanced melanoma in the last six years with the advent of targeted therapy and immunotherapy. For patients suitable for both treatments, we do not know which treatment to start first. There is emerging evidence that if you start with targeted therapy, it makes the tumour more responsive to immunotherapy. But we don’t know when to switch from one treatment to another.
We have shown that with a blood test, we can pick up circulating tumour DNA (ctDNA), which is tumour genetic material released from the tumour in to the blood. We can use this to monitor the response to treatment. We are now about to start the CACTUS study in which we will monitor patients on targeted therapy with dabrafenib and trametinib using ctDNA, and switch them to immunotherapy at the point when they are most likely to benefit. This is the first study of its kind in melanoma to use a biomarker to individualise/personalise treatment decisions in real time in patients on treatment, and we think it is a major advance. The study will initially run in four centres in the UK (Newcastle, Mount Vernon, Royal Marsden and Manchester) in February 2018, with a view to expanding internationally if we get a strong signal that it works. We are very excited about this technology and are looking to use it in a number of other ways to individualise advice and treatment decisions. More information to follow in the next few months.
Professor Richard Marais was presented with the Outstanding Research Award by the Society for Melanoma Research in Brisbane during the annual SMR conference in October 2017. This honour is to recognise an individual or group for highly impactful, major discoveries in the field of melanoma within the last five years.
Two of our young investigators have been honoured with a Conquer Cancer Foundation ASCO merit award at the Annual meeting in Chicago in June 2017. Only 12 abstracts are selected for presentation and discussion in this category so for both of them to achieve this is a huge honour. Well done and thanks to everyone that made this possible, it’s a real team effort.
Dr. Sara Valpione’s award was for her work leading an international group of collaborators in Europe, US and Australia, looking at retreatment of melanoma patients with targeted therapy. ‘Re-challenge with BRAF directed treatment: a multi-institutional retrospective study’. During the discussion it was recognised that the study results are expected to change practice and have a major impact on how patients are treated in the future.
Dr. Rebecca Lee’s work looked at blood borne biomarkers that can predict the risk of relapse in patients who have had curative surgery for melanoma. 'Use of circulating tumour DNA to predict survival in patients with resected high-risk stage II/III melanoma'. These preliminary data showed that if we test for a mutation in the blood that comes from the cancer (a "liquid biopsy") following surgery for high risk, early stage melanoma, if the mutation is detected then patients are at extremely high risk of relapse. This information can then be used to potentially identify early those patients in whom we might need to follow up more closely or to potentially consider more intensive treatment.
Jackie Mitchell has joined the group as a Research Coordinator. Jackie will manage our increasing portfolio of research, ensuring that all opportunities are maximised, interacting with Pharmaceutical Companies and Funders etc. She began working in the NHS as a midwife over 20 years ago and pursued her interest in research with an MSc in Population Health. This led to a full time career in health research in a variety of areas; however cancer research has always interested Jackie and with her experience in research management she will make a meaningful contribution to further developing the melanoma trials portfolio.
The study results have just been presented at the America Association of Cancer Research (AACR) meeting in Washington. This compared single agent with combination immunotherapy in people where melanoma has spread. We now know that combination therapy is a more effective treatment for many patients, and will be able to use these results to advise patients accordingly. However there remain a number of unanswered questions about how best to select those who need this treatment as many patients do just as well with one drug. The combination of two drugs is associated with significantly more toxicity.
Following on from discussions with NHS England, we have now resolved the issue about access to combination immunotherapy and targeted therapy for all eligible patients. Patients in the UK now enjoy better access than many other countries in Europe, and this is a testament to close discussion and interaction between senior UK clinicians and NHS England.
Three major new treatments have been approved by NICE and are currently funded by the Cancer Drugs Fund. The targeted therapy combination of dabrafenib and trametinib is suitable for patients with a BRAF mutation (approximately 50% of all patients) and is a significant advance over the previous standard of care. The immunotherapy combination of ipilimumab and Nivolumab is also appropriate for many patients. We are still awaiting the final results of trials but this is also set to become a standard of care for many patients.
The third treatment is TVEC, an injected treatment for patients where the melanoma has not spread to internal organs. Whilst there are a relatively limited number of patients who will be suitable for TVEC, the real excitement is that TVEC combined with other treatments seems to be very effective, and trials are ongoing to evaluate this further. So the last three months will be seen as a major turning point for access to treatment and improved outcomes for patients in the UK.
A recent British Journal of Healthcare ‘Comment’ article written by two of the team here in Manchester, Dr Fabio Gomes and Professor Paul Lorigan provides a succinct overview of the present state of melanoma management, treatment options and potential future directions for both melanoma and other cancers responsive to these treatments. Access PDF here.
The research programme in melanoma continues a pace, focusing on developing Personalised Medicine approaches to managing patients with melanoma. The aim is to analyse each individuals melanoma sample at a detailed molecular level before treatment, then monitor the patient closely on treatment using ‘liquid biopsies’ – highly sophisticated blood tests that can detect parts of the tumour DNA in the blood - to pick up at an early stage any changes in the tumour that suggest it is responding or becoming resistant to treatment. We have published our findings in the journal Cancer Discovery (Girotti et al, December 2015) and have a second paper accepted for publication, and have given presentations at a number of international meetings including the America Association for Cancer Research in April 2016. At present, we are continuing to evaluate this in clinical trials, with the plan to move it to standard of care as soon as possible.
Doctor Andrew Hudson and Doctor John Brognard (CRUK Manchester Institute) have shown that many of the current techniques used to search for cancer causing genes can miss their intended targets due to 'cold spots' that are skipped by these methods. This discovery will have major implications for how we do this type of research. Read the summary here.
Discrepancies in Cancer Genomic Sequencing Highlight Opportunities for Driver Mutation Discovery. Hudson AM, Yates T, Li Y, Trotter EW, Fawdar S, Chapman P, Lorigan P, Biankin AV, Miller C, Brognard J.Cancer Research. 2014 Sep 25. [Epub ahead of print]
Dr Amaya Virós, a clinician scientist based at the Cancer Research UK Manchester Institute, has been awarded a Wellcome Trust Intermediate Clinician Scientist Fellowship. The fellowship will allow Dr Virós to establish her own lab to carry out research into why older patients are less likely to survive following a melanoma diagnosis.
Dr Virós explains her project: “More than 80% of melanoma deaths occur in patients who are older than 50 years old, and mortality is specifically increasing in the elderly. Melanoma in the elderly is also more likely to progress. We will investigate why older people are more vulnerable to melanoma and if melanoma in the elderly is inherently more aggressive.”
Professor Marais, Director of the CRUK Manchester Institute, said: “The award by the Wellcome Trust is a reflection of her impressive achievements to date and her potential as a world-leading cancer researcher.”
This is an excerpt from the full article at MCRC website’s News section: http://www.mcrc.manchester.ac.uk/News?newsId=323
The melanoma team here in Manchester are part of a ground-breaking project that could result in the UK leading the world in genomic medicine. With Prof Marais at the CRUK Manchester Institute and colleagues at the Royal Marsden Hospital, Prof Lorigan is leading the UK Melanoma Group project linked to the 100K Genome Project being run by Genomics England Clinical Interpretation Partnership. We will carry out whole genome sequencing (WGS) on hundreds of melanoma patient samples linked to new treatments and rare melanoma subtypes. WGS allows us to look at all of the genes in the tumour and compare them to the patients’ normal tissue. It is the most detailed molecular analysis possible, essentially representing the blueprint for the functioning of a cell. With this, we expect to uncover new clues on how melanoma develops and how to treat it.
The 100,000 Genome Project is one of the biggest WGS projects in the world. The genetic material will come from cancer patients, patients with rare diseases (and two of their blood relatives) and also some patients with severe infections. The huge task to sequences the genomes should be completed by the end of 2017. Thus a massive database will be available for treatment and research with the intended outcome of better diagnostic capabilities and more effective and personalised treatments.
Metastasis is responsible for most of the cancer-related deaths and, among common tumour types melanoma is one with great potential to metastasize. It is critical to understand the mechanisms that mediate this process. This study used detailed epigenomic methods which analyse changes to all a cell's genetic material, combined with laboratory (in vitro) and melanoma patients' (in vivo) data. From this a protein was identified which exacerbates melanoma growth both in vitro and in vivo. Coincidentally it also confers more sensitivity of the tumour to targeted therapy. In the clinical setting, finding molecular biomarkers for predicting whether metastatic disease will develop or for determining prognosis is a huge advantage when selecting and developing treatments and planning patient care.
Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Vizoso M, Ferreira HJ, Lopez-Serra P, Carmona FJ, Martínez-Cardús A, Girotti MR (pictured), Villanueva A, Guil S, Moutinho C, Liz J, Portela A, Heyn H, Moran S, Vidal A, Martinez-Iniesta M, Manzano JL, Fernandez-Figueras MT, Elez E, Muñoz-Couselo E, Botella-Estrada R, Berrocal A, Pontén F, Oord JV, Gallagher WM, Frederick DT, Flaherty KT, McDermott U, Lorigan P, Marais R, Esteller M. Nat Med. 2015 Jun 1. doi: 10.1038/nm.3863. [Epub ahead of print]
Promising early data from a new drug developed by the CRUK Manchester Institute in collaboration with the Institute for Cancer Studies (Royal Marsden Hospital) and the Wellcome Foundation led to a publication in Cancer Cell 2015.
We were greatly encouraged by the results, and so with a£280,000 grant from our Melanoma Research Fund this new panRAF inhibitor is being trialled here and at the Royal Marsden Hospital. The first patient began their treatment in April 2015 at The Christie. Read the Cancer Cell summary here: Paradox breaking RAF inhibitors.
More on this and links to the guidelines are included via the 'Education Resources' section.
The results of the 'COMBI-V' trial were published in the New England Journal of Medicine on November 16th 2014. Dr. Lorigan was the Principal Investigator for this international study. The results showed definitively that a combination of BRAF and MEK inhibitors is superior to BRAF inhibitor alone (for patients suitable for targeted therapy with a BRAF inhibitor).
Combination therapy is licensed in the US but not yet in Europe. However, the good news is we are able to offer this treatment to patients by way of a 'Compassionate Use Programme'. This programme is established in the European Union for patients who have a disease with no satisfactory authorised therapies or who cannot enter a clinical trial. It is a way for them to access new treatment options under development.
Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. New England Journal of Medicine. 2014 Nov 16. [Epub ahead of print]
Professor Richard Marais and colleagues at the Cancer Research UK Manchester Institute have shown conclusively that UV light (ultraviolet) causes melanoma. Importantly, sunscreen protection reduces the risk but not completely. This further highlights the importance of also wearing protective clothing and a sun hat. The research was published in the most prestigious scientific journal Nature and received wide press coverage.
Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53. A. Viros, B. Sanchez-Laorden, M. Pedersen, SJ. Furney, J. Rae, K. Hogan, S. Ejiama, M. Girotti, M. Cook, N. Dhomen & R. Marais. Nature 511, 478-482 (24 July 2014)
The results of a two year Manchester based study looking at the emotional impact of a diagnosis of melanoma have been published in two journals. 'Asc Me' was funded entirely by the Melanoma Research Fund. As a result of the study we will be able to improve our identification of those people most at risk of anxiety and depression and offer them the appropriate support.
Prevalence and correlates of unmet supportive care needs in patients with resected invasive cutaneous melanoma. Molassiotis A, Brunton L, Hodgetts J, Green AC, Beesley VL, Mulatero C, Newton-Bishop JA, Lorigan P. Annals of Oncology. 2014 Oct;25(10):2052-8.
Assessing the impact of diagnosis and the related supportive care needs in patients with cutaneous melanoma. Stamataki Z, Brunton L, Lorigan P, Green AC, Newton-Bishop J, Molassiotis A. Support Care Cancer. 2014 Sep 5. [Epub ahead of print]
Scientific Papers' Summaries: for non-specialist and specialist readers
The latest relevant research papers can be viewed here. They are summarised and 'translated' into non-academic language. Summaries of important publications.