Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Dec;23(12):T259-T270.
doi: 10.1530/ERC-16-0251. Epub 2016 Oct 4.

Patient-derived tumour xenografts for breast cancer drug discovery

John W Cassidy  1 , Ankita S Batra  2 , Wendy Greenwood  2 , Alejandra Bruna  3
Affiliations
Free PMC article
Review

Patient-derived tumour xenografts for breast cancer drug discovery

John W Cassidy et al. Endocr Relat Cancer. 2016 Dec.
Free PMC article

Abstract

Despite remarkable advances in our understanding of the drivers of human malignancies, new targeted therapies often fail to show sufficient efficacy in clinical trials. Indeed, the cost of bringing a new agent to market has risen substantially in the last several decades, in part fuelled by extensive reliance on preclinical models that fail to accurately reflect tumour heterogeneity. To halt unsustainable rates of attrition in the drug discovery process, we must develop a new generation of preclinical models capable of reflecting the heterogeneity of varying degrees of complexity found in human cancers. Patient-derived tumour xenograft (PDTX) models prevail as arguably the most powerful in this regard because they capture cancer's heterogeneous nature. Herein, we review current breast cancer models and their use in the drug discovery process, before discussing best practices for developing a highly annotated cohort of PDTX models. We describe the importance of extensive multidimensional molecular and functional characterisation of models and combination drug-drug screens to identify complex biomarkers of drug resistance and response. We reflect on our own experiences and propose the use of a cost-effective intermediate pharmacogenomic platform (the PDTX-PDTC platform) for breast cancer drug and biomarker discovery. We discuss the limitations and unanswered questions of PDTX models; yet, still strongly envision that their use in basic and translational research will dramatically change our understanding of breast cancer biology and how to more effectively treat it.

Keywords: biomarker discovery; breast cancer; drug discovery; high-throughput screening; patient-derived tumour xenografts; pharmacogenomics; targeted therapies.

PubMed Disclaimer

Figures

Figure 1
Figure 1
High-throughput drug screen using patient-derived material. Figure 1 highlights high-throughput screening approaches using patient tumour material. (1) represents in vitro culture of tumour explants (for example as organoids/tumoroids). (2) represents the integrated PDTX:PDTC platform developed by our lab. In this strategy, patient tumour material is passaged and maintained in the murine host, and patient-derived tumour cells (PDTCs) are periodically dissociated for short-term ex vivo culture and high-throughput drug screens.
Figure 2
Figure 2
Biomarker discovery using PDTX models. Figure 2 highlights an unbiased approach for biomarker discovery. (1) a mixed cohort of PDTX models is screened with multiple compounds affecting different members of the same signalling pathway and are subsequently clustered based on responders and non-responders. Genomic correlates of drug response are computed before validation in vivo (2).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. 2003. Prospective identification of tumorigenic breast cancer cells. PNAS 100 3983–3988. (10.1073/pnas.0530291100) - DOI - PMC - PubMed
    1. Ali HR, Glont SS-E, Blows FM, Provenzano E, Dawson S-JS, Liu B, Hiller L, Dunn J, Poole CJ, Bowden S, et al. 2015. PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Annals of Oncology 26 1488–1493. (10.1093/annonc/mdv192) - DOI - PubMed
    1. Aparicio S, Caldas C. 2013. The implications of clonal genome evolution for cancer medicine. New England Journal of Medicine 368 842–851. (10.1056/NEJMra1204892) - DOI - PubMed
    1. Bashashati A, Ha G, Tone A, Ding J, Prentice LM, Roth A, Rosner J, Shumansky K, Kalloger S, Senz J, et al. 2013. Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling. Journal of Pathology 231 21–34. (10.1002/path.4230) - DOI - PMC - PubMed
    1. Bergamaschi A, Hjortland GO, Triulzi T, Sørlie T, Johnsen H, Ree AH, Russnes HG, Tronnes S, Mælandsmo GM, Fodstad O, et al. 2009. Molecular profiling and characterization of luminal-like and basal-like in vivo breast cancer xenograft models. Molecular Oncology 3 469–482. (10.1016/j.molonc.2009.07.003) - DOI - PMC - PubMed

Publication types

MeSH terms

Substances