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

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Greiner Bio-One North America, Inc. is announcing the creation of a patient-derived xenograft (PDX) model for inflammatory breast cancer (IBC) using magnetic 3D cell culture (M3D) research methods that mimic the current PDX model standard. This new and effective methodology will provide a more efficient approach to combat one of the most aggressive forms of breast cancer.

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-inflammatory breast 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 with non-inflammatory locally advanced breast cancer.

Translation of new therapies into the clinics to 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.

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

About this study

Cell types listed

  • Patient-derived xenograft (PDX) cancer cells

 

M3D System used

  • 24-well Bio-Assembler (levitation)
  • 96-well Bioprinting

 

Topics

  • Triple-negative inflammatory breast cancer
  • High-throughput screening
  • Personalized medicine
  • Patient-derived xenograft PDX
  • Spheroids
  • Organoids
  • 3D vs in vivo

 

Academic Authors, key opinion leaders (KOL) from:

  • MD Anderson Cancer Institute
  • University of Texas Health Science Institute at Houston
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