Human Plasma-Derived 3D Cultures Model Breast Cancer Treatment Responses and Predict Clinically Effective Drug Treatment Concentrations

Abstract

<jats:p>Lack of efficacy and a low overall success rate of phase I-II clinical trials are the most common failures when it comes to advancing cancer treatment. Current drug sensitivity screenings present several challenges including differences in cell growth rates, the inconsistent use of drug metrics, and the lack of translatability. Here, we present a patient-derived 3D culture model to overcome these limitations in breast cancer (BCa). The human plasma-derived 3D culture model (HuP3D) utilizes patient plasma as the matrix, where BCa cell lines and primary BCa biopsies were grown and screened for drug treatments. Several drug metrics were evaluated from relative cell count and growth rate curves. Correlations between HuP3D metrics, established preclinical models, and clinical effective concentrations in patients were determined. HuP3D efficiently supported the growth and expansion of BCa cell lines and primary breast cancer tumors as both organoids and single cells. Significant and strong correlations between clinical effective concentrations in patients were found for eight out of ten metrics for HuP3D, while a very poor positive correlation and a moderate correlation was found for 2D models and other 3D models, respectively. HuP3D is a feasible and efficacious platform for supporting the growth and expansion of BCa, allowing high-throughput drug screening and predicting clinically effective therapies better than current preclinical models.</jats:p>

Cellular Flocculation Using Concentrated Polymer Brush-Modified Cellulose Nanofibers with Different Fiber Lengths

“…Reports indicate that 3D cell culture is more conducive to drug development (Parkinson’s drugs, anticancer drugs, etc.) and bioengineering (regenerative medicine) than 2D cell culture. − …”

Reduction of Metastasis via Epigenetic Modulation in a Murine Model of Metastatic Triple Negative Breast Cancer (TNBC)

“…Likewise, in osteosarcoma, RNA-sequencing data suggested that SOX2 is underexpressed in 4SC-202-treated cells [ 38 ]. Here, in a 3D-scaffold model [ 13 ], the population of cells that express stem-like characteristics is small in the 4T1 TNBC model; about 5% of the total 4T1 population grown in the 3D scaffolds revealed a distinct CSC profile (CD44 high /CD24 low ), which significantly decreased after 4SC-202 treatment ( Figure 6 b,c). CD24 expression of the CD44 high population also showed reduced CD24 low expression with increasing concentrations of 4SC-202.…”

“…4T1 cells and MDA-MB-231 cells (0.4 × 106 cells/mL) were embedded in a plasma three-dimensional (3D) scaffold engineered through the cross-linking of fibrinogen into fibrin as previously described [ 13 , 14 ]. Briefly, plasma was mixed with 4T1 or MDA-MB-231 cell suspensions prepared in RPMI complete media followed by encapsulation into matrices that were fabricated using calcium chloride (CaCl 2 ) as a cross-linker and trans-4-(aminomethyl) cyclohexanecarboxylic acid (AMCHA) as a stabilizer, respectively.…”

Clinical applications of 3D normal and breast cancer organoids: A review of concepts and methods

“…44,53 Given variability across commercially distributed batches of Matrigel and collagen I (such as batch-to-batch variation in composition, concentration, or pH), efforts are ongoing to develop a standardized matrix for organoid culture with the goal of providing greater experimental control across patient-derived systems. 54,55 In addition, collagen gels can be engineered to specifically enhance certain ECM features such as alignment. 44 In parallel, synthetic hydrogels are being developed for the culture of stem cells and organoids, including for breast organoids, thus far in hydrogels of glycosaminoglycans.…”