The EurOPDX Consortium is an initiative of translational and clinical researchers from 16 academic cancer centres and universities across 10 European countries, with the common goal of creating a network of clinically relevant models of human cancer, and in particular patient-derived tumour xenograft (PDX) models.
A workshop organised by EurOPDX Consortium on "PDX models to interrogate open issues in clinical oncology and cancer precision medicine", will take place in Weggis, Switzerland on 3-5 October, 2016.
The high failure rate in oncology drug development is posing significant challenges and novel approaches, including improved preclinical studies, are required. The PDX are being increasingly recognised as clinically relevant preclinical models, as they maintain histopathological features and genetic profiles of the original patient tumours. Many PDXs have been established across Europe. It was crucial to join forces and build large collections of models to cover cancer heterogeneity, and to raise standards in the preclinical setting.
The main objectives of the EurOPDX Consortium are to:
- create a virtual collection of genomically and histologically characterised PDXs;
- harmonise working practices; and
- leverage the collection to investigate novel therapeutic strategies and uncover predictive biomarkers for personalised cancer treatment, through the performance of more effective and reproducible multicentre PDX studies with high predictability for success in the clinic.
Altogether, the EurOPDX Consortium displays a panel of more than 1,500 subcutaneous and orthotopic PDX models for more than 30 pathologies.
Through this collaborative academic effort and collaborations with pharmaceutical companies and small and medium-sized enterprises involved in drug development, the EurOPDX Consortium aims to reduce duplication of efforts in oncology drug development and raise PDX models as the cornerstone of precision cancer medicine.
The evolution to more effective preclinical trials will streamline clinical proof-of-concept, ultimately reducing attrition in oncology clinical trials.
To improve the robustness of data, preclinical studies need to be conducted with the rigour and challenges of clinical trials. The PDXs are today recognised as very relevant preclinical cancer models, however they are very time-consuming and consequently very expensive.
The PDX collection
The current collection of PDX models across the EurOPDX member institutions displays over 1,500 subcutaneous or orthotopic models for more than 30 different solid tumour types. One of the Consortium main objectives in the next few years will be to homogenise the characterisation of the models across the collection, following the validation and characterisation standards agreed by the Consortium.
The models will remain in the laboratories where they have been developed, and the goal is to promote and facilitate the exchange of models between centres for particular collaborative projects. To this end, the Consortium is working on a common Material Agreement Template to accelerate the legal aspects related to the exchange of PDX models and related materials.
The EurOPDX Consortium has 754 PDXs in colorectal cancer, 291 from primary tumours, 444 liver metastases, 4 lung metastases, 15 other metastases. In term of characterisation, 350+ are already characterised by transcriptome arrays and targeted sequencing, but also 150+ by WES and 250+ drug monitoring.
The EurOPDX Consortium has 235 PDXs in pancreatic cancer, 211 from primary tumours, 24 liver and other metastases. In term of characterisation, 120+ transcriptomic, 100+ CGH, 120+ WES, 20+ WGS, 70+ RNAseq, 70+ MiR.
The EurOPDX Consortium has 161 PDXs in breast cancer, 54 luminal, 89 triple negative, 18 HER2-positive. In term of characterisation, 90+ transcriptomic, 40+ CGH, 40+ WES, drug monitoring.
The EurOPDX Consortium has 71 PDXs in lung cancer, 59 NSCLC and 12 SCLC with ongoing characterisation.
The EurOPDX Consortium has 136 PDXs in skin melanoma, 3 from primary tumours, 133 subcutaneous and others metastases. In term of characterisation, 20+ WES, 40+ gene panel, drug monitoring.
The EurOPDX Consortium has 142 PDXs in ovarian cancer and 77 PDXs in endometrial cancer with ongoing characterisation.
The EurOPDX Consortium has 63 PDXs in head and neck cancer, 50 from primary tumours, 13 metastases with ongoing characterisation.
The EurOPDX Consortium has 52 PDXs in glioblastoma, 35 PDXs in sarcoma, 27 PDXs in renal cell cancer, 18 testicular cancer PDXs, 17 uveal melanoma PDXs and 12 PDXs from paediatric tumours.
Some of the ongoing projects within the EurOPDX Consortium
The Consortium is currently working on a pilot distributed Laboratory Management Information System, based on the Laboratory Assistant Suite already developed at the University of Turin, Italy, and in close collaboration with the Elixir Infrastructure. This system will allow live tracking by digital barcoding of all biobanking information and in vivo data, and the distributed system will permit direct sharing of this information across EurOPDX centres. Concomitant efforts include the availability in this common database of all characterisation and molecular profiling data.
The Consortium is currently finalising the discussions on common standards for the validation and characterisation of PDX models, following its workshop in November 2014 hosted by the Vall d'Hebron Institute of Oncology and dedicated to this topic. As a general principal, each model will be considered as a xenopatient, without the need for systematically comparing with the original patient tumour, as long as the characterisation and analyses performed for a patient at diagnosis will be available with proof of relevance to human disease. These analyses should be available for the passage shared, and fingerprinting generalised as quality control. Molecular profiling should be available in addition to this minimal characterisation. A publication detailing these considerations is in preparation.
A "Xenopatient Discovery Platform for the integrated Systems based Identification of Predictive Biomarkers for Targeted Therapies in Metastatic Colorectal Cancer", is led by Dr Annette Byrne at RCSI, in collaboration with EurOPDX members from the University of Turin and KU Leuven, as well as other partners. The ColoForetell project has received funding from Science Foundation Ireland, and commenced in December 2014.
Pilot multicentre trial - Ovarian and endometrial cancers
Among several starting pilot trials, this project is led by KU Leuven, with the objective to test new combinatorial strategies in a subset of ovarian and endometrial cancers. Targeted characterisation of multiple PDX models from 4 different EurOPDX centres and the Vall d'Hebron Institute of Research is being centralised at KU Leuven, before decision on inclusion or not in the in vivo study.
Breast cancer pharmacogenomics
Under the lead of Dr Alejandra Bruna at the CRUK Cambridge Institute, a pipeline to perform high-throughput single and combination drug screening assays in a feasible and cost-effective manner has been developed, by combining in vivo maintenance of human derived samples (as low passaged PDXs) with ex vivo short-term cultures (PDX cells or PDCs). The Consortium has comprehensively characterised this PDX_PDC integrated platform and shown it can successfully recapitulate patient-specific treatment and rationally predicted targeted treatment responses. Subsequently, the Consortium aims to expand the use of this approach to conduct preclinical experiments which mirror the planned clinical trials (co-clinical trials) and to identify novel synthetic lethality contexts, which can only be done using the integrated in vivo/high-throughput set up they have developed.