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New therapies for uveal melanoma

Periodic Reporting for period 3 - UM Cure 2020 (New therapies for uveal melanoma)

Reporting period: 2019-01-01 to 2020-06-30

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.
As we are reaching the end of the project, the work performed under UM Cure 2020 already yielded important results:
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 219 metastatic UM samples from 149 patients, with matched samples for 46 patients. These samples have been used for the establishment of relevant preclinical models and characterisation of metastases and primary tumours;
2) We have evaluated in vitro in metastasis-derived cell lines over 60 combinations of targeted drugs (and single drugs), based on the knowledge of pathways altered in UM metastases. Pharmacological evaluation of the best in vitro combinations is still ongoing in vivo in patient-derived xenograft (PDX) mouse models of UM metastases. We hope to identify combinations showing a good efficacy in vivo, that would be further evaluated in a clinical trial beyond the project to offer patients with new treatments opportunities. This is our overall goal ;
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, Institut Curie has constituted a collection of over 30 liver metastasis-derived PDX models, which are used for in vivo pharmacological evaluations as mentioned above;
4) Different omics and screening approaches have already been performed, with the objective to decipher the genetic alterations and dysregulated signalling pathways in metastatic UM. Our findings first show that the progression to a metastatic disease is associated with recurrent copy number changes, but with neither additional oncogenic mutation nor tumour heterogeneity. Tumour heterogeneity as a possible mechanism for therapeutic resistance of the liver metastases can thus be ruled out. Although no actionable target is coming out of NGS analyses, the identification of a subset of tumours characterized by MBD4 inactivation and an outlier response to immunotherapy represents an important finding. More cases are needed to establish MDB4 as a biomarker of response to immunotherapy. Further MBD4 was recently described as a predisposition gene for UM conferring a relative risk for UM of almost 10-fold (Derrien A.-C. Rodrigues M. et al., JNCI 2020). The novel targets and biomarkers specific to UM metastases identified are currently undergoing validation. Finally, we are performing a thorough analysis of the immune microenvironment of UM tumours towards the application of immunotherapy approaches;
5) We are widely disseminating our project objectives and results in order to increase awareness, in particular through the project website (www.umcure2020.org) and social media platforms (Facebook, Twitter and YouTube channel,@UMCURE2020). Our brochure raising awareness on UM has been widely distributed through patients, patient advocates and clinicians. The new empowered and engaged UM patient community MPNErare is now counting over 450 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.
Our project has been unique in boosting 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.
- Collected samples are used to deliver a deep characterisation of liver metastases at genetic, proteomic, and immunological levels. We have been 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. New actionable target hypotheses obtained through additional approaches are still under validation;
- We have also extended our panel of preclinical models that typify the disease, with genetically-modified models still under development;
- Many preliminary findings from in vitro and in vivo evaluation of single drugs and combinations are already available. Our last series of in vivo experiments in mouse PDX models of UM metastases is starting.
We still hope by the end of the project to have sufficiently promising preclinical data with one or more single drugs or combinations to trigger further research, in collaboration with pharmas of biotechs developing these molecules, and 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.
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 a major social impact of the UM Cure 2020 project.