Clinically relevant inflammatory breast cancer patient-derived xenograft-derived ex vivo model for evaluation of tumor-specific herapies.
Using Greiner Bio-One Magnetic 3D Cell Culture technology
Inflammatory breast cancer (IBC) is a rare and aggressive presentation of invasive breast cancer with a 62% to 68% 5-year survival rate. It is the most lethal form of breast cancer, and early recognition and treatment is important for patient survival. Like non-inflammatorybreast cancer, IBC comprises multiple subtypes, with the triple-negative subtype being overrepresented.
Although the current multimodality treatment regime of anthracycline- and taxane-based neoadjuvant therapy, surgery, and radiotherapy has improved the outcome of patients with triple-negative IBC, overall survival continues to be worse than in patients withnon-inflammatory locally advanced breast cancer. Translation of new therapies into the clinics o successfully treat IBC has been poor, in part because of the lack of in vitro preclinical models that can accurately predict the response of the original tumor to therapy.
We report 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. We demonstrate a high degree of similarity in drug response profile 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.
University of Texas
MD Anderson Cancer Center
patient-derived xenograft (PDX) of triple negative inflammatory breast cancer
Cancer, breast cancer
Patient-derived xenograft (PDX)
High-throughput screening (HTS)
Comparison of 3D vs. in vivo
Compared 3D vs. in vivo with virtually no difference between 3D in vitro and in vivo:
- Protein expression
- Coding genes or gene expression
HTS of 200 compounds NCI library – in vitro only because it is too costly to be performed PDX in vivo models.
8 compounds 3D vs. in vivo comparison and results were equivalent
Validated for magnetizing cells from in vivo tissue
This MD Anderson group tried to generate 3D in vitro models with other techniques, such as round Scivax plates and round bottom, but were not able to generate reproducible results. Maintaining the culture on the magnet at least overnight to push the cells together made a significant difference in the success of this work
Nanoshuttle™, again, did not have any effect on the cultures – in vivo without Nanoshuttle™ showed the same protein and gene expression as in vitro with Nanoshuttle™.
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