September 15, 2016
Featured Cell article - Breast cancer PDX-derived cells as drug-screening platform
Dr. Alejandra Bruna and colleagues, from Prof. Carlos Caldas laboratory at the Cancer Research UK Cambridge Institute (CI), recently published in Cell a new experimental platform using patient-derived tumour xenografts (PDTXs) of breast cancer (BC) in high-content preclinical drug screening. This work represents an important advance in the potential of PDTXs for personalised medicine, allowing for a rapid, cost effective testing in BC’s with a wide range of different therapeutic possibilities.
Initially, the authors deeply molecularly characterised most of their PDTX samples, at different passages, and the matched originating cancer, and showed PDTXs resemble at the copy number, mutational, epigenetic and transcriptomic levels the originating tumour sample. Significantly, these molecular and histological features remain stable through serial passaging of the PDTX samples in the mouse. Bruna et al. also showed PDTXs are communities of clones of similar composition and architecture to that that is found in the clinical population and matched originating tumour sample. This unique feature positions BC PDTXs as an improved preclinical model in drug development and for the study of molecular mechanisms of drug response and resistance.
One of the main limitations of PDTXs is that they don’t support the powerful advances of high-throughput drug testing. The authors overcame this limitation by developing the PDTC/PDTX platform, which uses short-term cultured PDTX cells (or PDTCs) for ex vivo high-throughput single and drug-drug combination testing. The reproducibility and specificity of the dataset supports its robustness and biologically relevance. Significantly, ex vivo PDTCs drug responses are highly correlated with in vivo responses, suggesting that PDTCs can be used as a drug-screening platform prior to testing drugs in vivo, thus contributing to reducing the number of mice used in experiments and complying with the 3R rules. In addition, Bruna et al. nicely showed that PDTCs also retain the intra-tumour heterogeneity and clonal architecture of the original patient samples.
The authors used a large biobank of highly annotated BC PDTX samples to conduct the study. This large biobank is being maintained and expanded at the CI and is currently one of the largest BC PDTX biobanks in the world in the academic setting. It is currently composed of n=93 models, from which some were initially established in other EurOPDX centres: Institut Curie (Paris, France, PI: Dr. Elisabetta Marangoni), the Vall d'Hebron Institute of Oncology (Barcelona, Spain, PI: Dr. Violeta Serra) and the Netherlands Cancer Institute (Amsterdam, The Netherlands, PI: Dr. Jos Jonkers).
This initiative led by the Caldas laboratory in Cambridge represents the first biobank of EurOPDX models with extensive molecular and drug response annotation that can be easily browsed in a public web portal developed in the CI (http://caldaslab.cruk.cam.ac.uk/bcape).
This publication also supports one of the EurOPDX main objectives of biobanking and sharing large numbers of PDTX models for easy access to the scientific community, and generalising the use of state-of-the-art PDX-derived in vitro models.
Link to the article: http://www.sciencedirect.com/science/article/pii/S0092867416311382