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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - UM Cure 2020 (New therapies for uveal melanoma)

Teaser

Summary

Uveal Melanoma (UM) is a rare intraocular disease with an incidence of five cases per million individuals per year in Europe. While current treatments for primary UM are effective, up to 50% of UM patients develop metastases within a median time of 2.4 years most often in the liver. Although we can identify the patients at risk on the basis of new discoveries regarding the genetic and molecular background of UM, there is still no therapy to either prevent or treat UM metastases. There is an urgent need to accelerate research on UM, allowing the development of efficient therapies for patients with metastases.
The overall goal of the UM Cure 2020 consortium is to combine the efforts of several European Centres of Excellence in clinical ocular oncology and basic research with patient organisations and innovative companies to develop new therapeutic approaches to treat metastatic UM, and share this new knowledge efficiently.
We propose an innovative concept placing the patient central in therapy development. While our major objective is to identify new potential therapeutic strategies for metastatic UM, the centre of our approach is to characterise the tumour tissue from UM patients with metastases, in order to define actionable targets. We will develop tumour-specific preclinical models and biomarkers to evaluate single drugs or their combinations. The most promising drugs will then be tested in clinical trials, outside the frame of the project. In addition, we aim at connecting directly with UM patients throughout Europe, providing them with up-to-date information on new treatments for their disease and possibilities to get involved. Patients are therefore central in each of our research steps up until the dissemination and implementation of the results.

Work performed

The work performed during the first 3 years already yielded important results for the achievement of our specific objectives:
1) We harmonised the collection of UM patients biosamples (primary tumour, metastases and matched blood whenever possible) across the 4 reference centres (Institut Curie, University of Liverpool, Leiden University Medical Centre and Jagiellonian University), and set-up a virtual common database now registering 149 metastatic UM samples from 50 patients, with matched samples for 19 patients. Prospective collection is ongoing. These samples are used for the establishment of relevant preclinical models and characterisation of UM metastases;
2) We have evaluated in vitro in metastasis-derived cell lines over 40 combinations of drugs (and single drugs). In vivo validation in patient-derived xenograft (PDX) mouse models is ongoing. An additional innovative approach is also ongoing under the lead of the SME PEP-Therapy;
3) Both in vitro and in vivo preclinical models recapitulating the pathophysiology of UM progression and metastases formation were sorely lacking. To this aim, a series of patient-derived and genetically-modified models are being developed in mouse and zebrafish. So far, we have established two new metastasis-derived cell lines, and Institut Curie has constituted a collection of over 30 liver metastasis-derived PDX models, which will be used for in vivo pharmacological evaluations as mentioned above;
4) Different omics and screening approaches are ongoing, with the objective to decipher the genetic alterations and dysregulated signalling pathways in metastatic UM, and the characteristics of the UM immune landscape, and identify novel targets and biomarkers specific to UM metastases. We published the first genome wide association study in UM (Mobuchon et al., NPJ Gen Med 2017), which allowed to identifying TERT/CLPTM1L as a susceptibility genetic region for developing primary UM. We described the detailed genetic landscape of the metastatic disease, showing extremely low tumour heterogeneity in UM metastases. However, we identified an outlier patient associated with an inactivation of MBD4 and a near complete response to immune checkpoint therapy (Rodrigues et al., Nat Commun 2018). One percent of UM cases may be inactivated for MBD4, and it is possible that these patients will strongly benefit from immunotherapy. Several other studies are ongoing and will deliver many more results during the last two years of the project, in particular thanks to our phospho-profiling approach with the technology of the SME PamGene;
5) Finally, we are widely disseminating our project objectives and preliminary results in order to increase awareness of the project towards our stakeholders, in particular through the project website (www.umcure2020.org) and social media platforms (Facebook, Twitter and YouTube channel,@UMCUR2020). Our partner Melanoma Patient Network Europe has been creating an empowered and engaged UM patient community (MPNErare), with already over 300 members across Europe. These activities will support our ultimate exploitation goal, i.e. the initiation of UM-dedicated clinical trials sponsored by academia or pharma.

Final results

Our project boosts preclinical and translational research on UM, towards a better characterisation of UM liver metastases that was lacking due to the rarity of the disease, and a better management of the metastatic form of this rare tumour. Our efforts also focus on primary UM, to improve prognostication and management of patients, as from diagnosis.
- Firstly, we are building an unprecedented collection of UM samples from primary tumours, metastases, and blood samples. Moving forward, we continue to emphasise the need for matched samples to better understand the pathophysiology of UM.
- Collected samples are used under the project (and will of course be used beyond), in particular to deliver a deep characterisation of liver metastases at genetic, proteomic, and immunological levels. We are describing for the first time the genetic landscape of UM metastases, with low heterogeneity apart from a subgroup of patients with MBD4 inactivation that may benefit from immunotherapy. This is being further investigated, and may have important impacts for patients displaying metastases with this alteration. Results from additional characterisations of UM liver metastases will be available by project closure and may bring new actionable target hypotheses.
- We have also extended our panel of preclinical models that typify the disease, with genetically-modified models still under development and expected to be available by project end.
- Many preliminary findings from in vitro and in vivo evaluation of single drugs and combinations are already available, and preclinical data will be strengthened in the next 2 years.
We believe that by the end of the project we will have sufficiently strong and promising preclinical data with one or more single drugs or combinations to trigger the initiation of a clinical trial dedicated to patients with liver metastases of UM. All results, even negative, will be published to avoid duplication of efforts and benefit further research on UM to build on our project\'s results.
Patients are involved in all aspects of our research, in particular through the building of the MPNErare forum, a UM patient community across Europe that has grown tremendously since project start. Increasing knowledge exchange and the empowerment of patients constitutes an important social impact of the UM Cure 2020 project, beyond the main objective to initiate a UM-dedicated clinical trial and improve disease management and treatment.