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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - EDIReX (EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts)

Teaser

Summary

Counteracting high failure rates in oncology drug development and providing optimal therapeutic management of cancer patients require preclinical models that properly recapitulate the complexity and diversity of human tumours. Patient-derived tumour xenografts (PDXs), established by transplanting tumour fragments into immunodeficient mice, are being widely embraced by the scientific community as reliable preclinical tools for efficient drug development and tumour biology studies.
The EurOPDX Consortium, established in 2013 by cancer researchers establishing and working with PDX models, is now teaming up with other key academic and SME partners to build the EurOPDX Research Infrastructure (www.europdx.eu). Our overall goal is to establish a cutting-edge distributed European infrastructure offering free-of-charge access to PDX models and associated data and services for academic and industry cancer researchers.
We are integrating and curating a collection of over 1,000 models established and validated by EurOPDX members in the new EurOPDX Data Portal (https://dataportal.europdx.eu). The Data Portal allows efficient and user-friendly query and visualisation of clinical, molecular and pharmacological annotation of the models. Access by the 6 nodes of the infrastructure will include the distribution of cryopreserved samples to academic laboratories, the structured biobanking of user-developed models, and the performance of drug efficacy studies in particular for oncology SMEs. To ensure interoperability in services, we are establishing and applying standard procedures for PDX quality control, health monitoring, long-term storage and therapeutic mouse trials. Access is available through a grant programme, with 3 calls open in the frame of this 4-year project.
We aim to ensure the sustainability of this new infrastructure. In this objective, we are also preparing for the future provision of innovative services such as orthotopic and humanised PDX models, the use of multimodal imaging techniques, as well as in vitro PDX-derived cells. Overall, the EurOPDX Research Infrastructure activities and services will contribute to more reliable and predictable preclinical studies and therefore more efficient development of new therapeutic strategies for cancer patients.

Work performed

\"During the first 18 months of the project, we have achieved most preparatory work to provide access to PDX models to users of the EurOPDX Research Infrastructure:
- After a first prototype demo at the 2nd EurOPDX Workshop in October 2018, the new version of our repository of models EurOPDX Data Portal) has been launched during the summer 2019 (https://dataportal.europdx.eu). The Data Portal is powered by the PDX Finder, a global repository developed by our project partner EMBL-EBI together with The Jackson Laboratory. The Data Portal currently links molecular data to the cBioPortal, an open-source tool widely used by the cancer research community to explore cancer genomics data. Later during the project, data will be explorable in a tool for 3D visualization;
- As of September 2019, the Data Portal contains 880+ PDX models with associated data (cytogenics, mutations, drug dosing studies, patient treatment);
- To ensure interoperability between the 6 nodes of the infrastructure and increase the quality of models and samples, we have established standards operating procedures (SOPs) for the biobanking of PDXs and their quality control. In particular, the first SOP to be finalised was for health monitoring of animal facilities and models, which is often causing problems upon exchange of PDX models between scientists. SOPs for the performance of in vivo drug efficacy studies are ongoing;
- We also established the procedures for application to our grant programme and selection of successful applicants (see https://www.europdx.eu/europdxri-ta);
- The 1st call for free-of-charge was launched on 31st October 2018 and led to the selection of 6 user projects. They will correspond to a total of 31 PDX models biobanked according to our SOPs. 4 projects will received cryopreserved samples from PDX models selected in the EurOPDX collection (\"\"SAMPLE\"\" access), while two projects will trigger the biobanking of user-developed models (\"\"DEPOSIT\"\" access). The latter will be stored in one of the 6 nodes and displayed on the EurOPDX Data Portal, therefore made available to others. The biobanking for the 6 selected projects is starting;
- Finally, the project and our activities have been widely disseminated through our new website (www.europdx.eu), our Twitter acccount (@EurOPDX), and presentation to conferences. Feedback from our External Advisory Board members, as well as from users, will allow us to put together in the next months a solid sustainability strategy and further improve services provision.\"

Final results

Until about 18 months ago, the practice of exchange of data on PDX models was only following ad-hoc informal procedures, quite frequently sending Excel files only, with no thorough unification of format and semantics, and no centralized and harmonized comprehensive information on the establishment and characterization of each particular PDX model. With the increase in PDX models and providers this process was not sustainable anymore, for the effective development of collaborations between cancer researchers, and even less in the frame of the set-up of an infrastructure for research on PDX models. Thanks to our IT partners and the development of the PDX Finder (launched April 2018) and the EurOPDX Data Portal, we are now providing cancer researchers with a gateway to distributed collections of established and validated models. This will greatly improve PDX collaborative research.
In addition, standards in the field have been lacking. The establishment of our SOPs and the exchange in the near future with similar initiatives to reach global standards will have a great impact on the reliability and reproducibility of preclinical data using PDXs.
We are also testing the provision of more innovative services. Our integrated PDX platform would for instance have the possibility to pre-screen a large number of models in vitro with our SME partner Ocello, before in vivo validation only on a selected panel of PDXs.
In summary, the EurOPDX Research Infrastructure is preparing to become a reference for preclinical testing of new therapeutic interventions in Europe, improving and accelerating preclinical oncology research in Europe and worldwide.