Clinically relevant inflammatory breast cancer patient-derived xenograft–derived ex-vivo model for evaluation of tumor-specific therapies.

In a study published in PLoS ONE, Greiner Bio-One reports the generation of a preclinical IBC patient-derived xenograft (PDX)-derived ex-vivo (PDXEx) model and show that it closely replicates the tissue architecture of the original PDX tumor harvested from mice. The gene expression profile of our IBC PDXEx model had a high degree of correlation to that of the original tumor. This suggests that the process of generating the PDXEx model did not significantly alter the molecular signature of the original tumor.

Also, there was a high degree of similarity in drug response profile demonstrated between a PDX mouse model and our PDXEx model generated from the same original PDX tumor tissue and treated with the same panel of drugs, indicating that our PDXEx model had high predictive value in identifying effective tumor-specific therapies. Finally, we used our PDXEx model as a platform for a robotic-based high-throughput drug screen of a 386-drug anti-cancer compound library. The top candidates identified from this drug screen all demonstrated greater therapeutic efficacy than the standard-of-care drugs used in the clinic to treat triple-negative IBC, doxorubicin and paclitaxel.

Our PDXEx model is simple, and we are confident that it can be incorporated into a PDX mouse system for use as a first-pass screening platform. This will permit the identification of effective tumor-specific therapies with high predictive value in a resource-, time-, and cost-efficient manner. It was concluded that there is value in M3D combined with ex-vivo cultures for enabling the evaluation of drug efficacy using a high-throughput screening strategy.

 

Key Findings

In this work, magnetic 3D bioprinting provided key experimental advantages, with its rapid, relatively easy, and reproducible method to bioprint 3D cultures in high throughput. Here are key points:

• Comparison of in vivo PDX vs. in vitro bioprinted 3D with virtually no difference between 3D in vitro and in vivo (Morphology, Protein expression, Coding genes or gene expression, Dose-response)
• High-throughput screening (HTS) of 200 compounds NCI library – in vitro only because it is too costly to be performed PDX in vivo models.
• Dose-response comparison in vitro 3D vs. in vivo PDX comparison with 8 compounds where results were equivalent.
• Validated method for magnetizing cells from in vivo tissue
• Validated method for immunohistochemistry using M3D