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

Abstract

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. 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.

Progress for Immunotherapy in Inflammatory Breast Cancer and Emerging Barriers to Therapeutic Efficacy

“…Further, unlike other breast cancers, there are relatively few preclinical models of IBC. Though patient-derived xenograft models and patient-derived xenograft-derived spheroids of IBC have been reported, these models rely on immune-compromised mice and/or ex vivo culture conditions, limiting their utility for studies in tumor immunology [ 85 , 86 ].…”

Three‑dimensional models to study breast cancer (Review)

“…Among these methods, the magnetic levitation method inserts magnetic nanoparticles into the cells for assembling 3D models (39). These models allow the formation of spheroids from single-tumor BC cell lines such as MDA-MB-231, Hs785bst and Hs371.t, or their co-cultivation with human pulmonary fibroblast cell lines such as SUM159 (40) and, cells from patient-derived xenografts (PDXs) (41). In all these models, preservation of tissue architecture and the expression profile of key biomarkers from the original tissue was observed (40,41).…”

“…These models allow the formation of spheroids from single-tumor BC cell lines such as MDA-MB-231, Hs785bst and Hs371.t, or their co-cultivation with human pulmonary fibroblast cell lines such as SUM159 (40) and, cells from patient-derived xenografts (PDXs) (41). In all these models, preservation of tissue architecture and the expression profile of key biomarkers from the original tissue was observed (40,41). A major advantage of this approach that it is important to emphasize is its capability to develop spheroids in a short period of time; however, in terms of challenges concerning its implementation, it is important to mention that specialized instrumentation and particular laboratory skills are required (42).…”

Engineering Biological Tissues from the Bottom-Up: Recent Advances and Future Prospects

“…Bottom-up tissue engineering is not only widely used in tissue manufacturing and drug screening, but also provides a new technological approach for studying the mechanisms of angiogenesis and tumor cell growth [148,[151][152][153]. Inflammatory breast cancer (IBC) is a rare special type of breast cancer [148,154,155]. Currently, researchers are using bottom-up tissue engineering for cancer treatment.…”

“…Thus, the researchers demonstrated an in vitro (PDXEx) model of IBC PDX derived from the cellular environment released by mouse PDX tumors, which were similar to that of the original PDX tumor. The PDXEx model was made by using the magnetic assembly method (Figure 25A) [154]. Firstly, breast cancer tumors taken from mice were chopped up so that the contents were released completely.…”