What makes orthotopic patient-derived xenograft (O-PDX) models more clinically relevant than traditional patient-derived xenograft (PDX) or cell-derived xenograft (CDX) models?

Patient-derived xenograft orthotopic models are more clinically relevant than traditional PDX or CDX models because they1-4:

Preserve the histological architecture, stroma construction5-8, and gene-expression or mutation status of the original tumor tissue.7-10

Replicate the human tumor microenvironment (TME), which is critical to cancer progression and metastasis, and for assessing therapies that involve components of TME.5

Can predict the development of resistance to first-line therapy and response to second-line therapy – before these events are observed in patients.7,11

Patient-derived xenograft orthotopic models have gained prominence in basic and translational oncology research.5,12

1 Byrne AT, Alférez DG, Amant F, et al. Interrogating Open Issues in Cancer Precision Medicine with Patient-Derived Xenografts. Nat Rev Cancer. 2017;17(4):254-268.
2 DeRose YS, Wang G, Lin YC, et al. Tumor Grafts Derived from Women with Breast Cancer Authentically Reflect Tumor Pathology, Growth, Metastasis and Disease Outcomes. Nat Med. 2011;17(11):1514-1520.
3 Joo KM, Kim J, Jin J, et al. Patient-Specific Orthotopic Glioblastoma Xenograft Models Recapitulate the Histopathology and Biology of Human Glioblastomas In Situ. Cell Rep. 2013;3(1):260-273.
4 Du Q, Jiang L, Wang XQ, Pan W, She FF, Chen YL. Establishment of and Comparison Between Orthotopic Xenograft and Subcutaneous Xenograft Models of Gallbladder Carcinoma. Asian Pac J Cancer Prev. 2014;15(8):3747-3752.
5 Long JE, Jankovic M, Maddalo D. Drug Discovery Oncology in a Mouse: Concepts, Models and Limitations. Future Sci OA. 2021;7(8):FSO737.
6 Nakano, K., Nishizawa, T., Komura, D., Fujii, E., Monnai, M., Kato, A., Funahashi, S. I., Ishikawa, S., & Suzuki, M. (2018). Difference in Morphology and Interactome Profiles Between Orthotopic and Subcutaneous Gastric Cancer Xenograft Models. J of Toxicologic Pathology, 31(4), 293–300.
7 Julien S, Merino-Trigo A, Lacroix L, et al. Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer. Clin Cancer Res. 2012;18(19):5314-5328.
8 Walters DM, Stokes JB, Adair SJ, et al. Clinical, Molecular and Genetic Validation of a Murine Orthotopic Xenograft Model of Pancreatic Adenocarcinoma Using Fresh Human Specimens. PLoS One. 2013;8(10): e77065.
9 Zhao X, Liu Z, Yu L, et al. Global Gene Expression Profiling Confirms the Molecular Fidelity of Primary Tumor-Based Orthotopic Xenograft Mouse Models of Medulloblastoma. Neuro Oncol. 2012;14(5):574-583.
10 Shankavaram UT, Bredel M, Burgan WE, Carter D, Tofilon P, Camphausen K. Molecular Profiling Indicates Orthotopic Xenograft of Glioma Cell Lines Simulate a Subclass of Human Glioblastoma. J Cell Mol Med. 2012;16(3):545-554.
11 Tran Chau, V., Liu, W., Gerbé de Thoré, M., Meziani, L., Mondini, M., O’Connor, M. J., Deutsch, E., & Clémenson, C. (2020). Differential Therapeutic Effects of PARP and ATR Inhibition Combined with Radiotherapy in the Treatment of Subcutaneous Versus Orthotopic Lung Tumor Models. British J of Cancer, 123(5), 762–771.
12 Killion, J J, Radinsky, R, Fidler, I J. Orthotopic Models are Necessary to Predict Therapy of Transplantable Tumors in MiceCancer Metastasis Rev. 1998;17:279–284 https://doi.org/10.1023/A:1006140513233.