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EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts

Periodic Reporting for period 2 - EDIReX (EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts)

Reporting period: 2019-08-01 to 2021-01-31

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 access to PDX models and associated data and services for academic and industry cancer researchers, notably through free-of-charge trans-national access.
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 includes 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 have established and are 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.
Despite the delays encountered as a consequence of the successive COVID-19 lockdowns, we are in a very good position to deliver on the set-up of the new EurOPDX Research Infrastructure providing high quality preclinical cancer research models and results for EU and global cancer researchers. In particular:
- Our repository of models EurOPDX Data Portal (https://dataportal.europdx.eu) now includes over 1,000 curated PDX models from 9 different European. Research centres and 10 cancer diagnoses. 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 a EurOPDX instance of 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 innovative tool for 3D visualization;
- 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. Our health monitoring procedure pertaining to animal facilities and PDX models is already available on our website (www.europdx.eu/standards) whereas other standards will be published during RP3. The nodes are also all equipped with the same laboratory information management system LAS (Laboratory Assistant Suite), used to track the biobanking and intervention studies data;
- The standards established are applied in an unprecedented cross-validation study performed by the 6 nodes and additional centres to compare results using the same models and same drugs across centres and patient-derived platforms;
- Thanks to our procedures established to manage the trans-national access grant programme and selection of successful applicants (see https://www.europdx.eu/europdxri-ta) we have run 3 different calls for proposals with 4 deadlines. This led to the selection of 18 user projects that are ongoing, with most experiments to be completed in the last phase of the project;
- Finally, the project and our activities have been widely disseminated through our new website (www.europdx.eu) our Twitter account (@EurOPDX), and presentation to conferences. Feedback from our External Advisory Board members, as well as from users, allowed us to already define a solid sustainability strategy.
Until about 3 years 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. Of note, our results in collaboration with the US PDX network PDXNet published in Nature Genetics early 2021 (Woo, Giordano et al.) bolster the value of PDXs as representative models for preclinical cancer research.
We are also testing in the project 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.
Snapshot of the EurOPDX Data Portal, the public repository for EurOPDX patient-derived xenografts