Subcutaneous PDX models rarely produce metastasis in mice, nor do they simulate the initial tumor microenvironment, with engraftment rates of 40-60%.
For drug development studies, expansion of mice after the F3 generation is often utilized after ensuring that the PDX has not genetically or histologically diverged from the patient’s tumor.
[4] Researchers are beginning to attribute the reason that only 5% of anti-cancer agents are approved by the Food and Drug Administration after pre-clinical testing to the lack of tumor heterogeneity and the absence of the human stromal microenvironment.
[13] As a result, numerous studies have found that PDX models exhibit similar responses to anti-cancer agents as seen in the actual patient who provided the tumor sample.
Humanized-xenograft models are created by co-engrafting the patient tumor fragment and peripheral blood or bone marrow cells into a NOD/SCID mouse.
[3] The co-engraftment allows for reconstitution of the murine immune system, giving insight into the interactions between xenogenic human stroma and tumor environments in cancer progression and metastasis.
For example, the immune system could be 'hyper-activated' due to exposure to mouse tissues in a similar fashion to graft versus host disease.
Contreras-Zarate MJ et al. developed and characterized novel heterogeneous and clinically relevant human brain metastasis breast cancer PDXs (BM-PDXs) to study mechanisms of brain metastatic colonization, with the added benefit of a slower progression rate that makes them suitable for preclinical testing of drugs in therapeutic settings.
[21] In 2012, a study established 27 colorectal PDX models that did not diverge from their respective human tumors in histology, gene expression, or KRAS/BRAF mutation status.
[24] Researchers initially focused on using pancreatic PDX models for drug studies to improve the process to develop predictive and pharmacodynamics end points for several molecularly targeted therapies.
[25][26] Pancreatic PDX models have shown anti-mesothilin CAR-T cells (T-cells modified with a chimeric antigen receptor) to suppress cancer growth.
The PDXs retained the genotype and phenotype of patient tumors, and exhibited substantial infiltrative growth and metastasis to distant organs including the bone marrow.
[29] In vitro cell culture models of glioblastoma, although valuable, can not fully replicate the complexity of the disease since there is a clear lack of the brain microenvironment and clonal selection.
[3] The scientific community is trying to tackle these challenges mutualising efforts and exchanging models and expertise to avoid duplication: academic networks have sprung in Europe[36] and USA,[37] and the Horizon 2020 program is funding a new Research Infrastructure[38] providing standardised services and resources, with the goal of improving reproducibility and open access to resources and services.
[40] PDX models can also take significant time to create, which may pose a challenge to patients with advanced stages of cancer.