Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Among the key challenges in developing effective therapeutics is the poor translation of preclinical models used in the drug discovery pipeline. This leaves drug attrition rates and costs at an unacceptably high level. Previous work has highlighted the discrepancies in therapeutic response between current in vitro and in vivo models. To address this, we conducted a comparison study to differentiate the carboplatin chemotherapy response across four different model systems including 2D monolayers, 3D spheroids, 3D ex vivo tumors and mouse xenograft models. We used six previously characterized EOC cell lines of varying chemosensitivity and performed viability assays for each model. In vivo results from the mouse model correlated with 2D response in 3/6 cell lines while they correlated with 3D spheroids and the ex vivo model in 4/6 and 5/5 cell lines, respectively. Our results emphasize the variability in therapeutic response across models and demonstrate that the carboplatin response in EOC cell lines cultured in a 3D ex vivo model correlates best with the in vivo response. These results highlight a more feasible, reliable, and cost-effective preclinical model with the highest translational potential for drug screening and prediction studies in EOC.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer
Using a panel of six EOC cell lines, we show that previously characterized carboplatin response from 2D cultures differs significantly from the in vivo response of the xenograft mouse model
Treatment response in the xenograft model varied significantly from the 2D culture ranking (Supplementary Table S1); a positive correlation of 2D sensitivity with the in vivo response was found in 3/6 EOC cell lines (Table 1)
Summary
Among the key challenges in developing effective therapeutics is the poor translation of preclinical models used in the drug discovery pipeline. Our results emphasize the variability in therapeutic response across models and demonstrate that the carboplatin response in EOC cell lines cultured in a 3D ex vivo model correlates best with the in vivo response. These results highlight a more feasible, reliable, and cost-effective preclinical model with the highest translational potential for drug screening and prediction studies in EOC. The current drug discovery pipeline is dependent on 2D cell culture model systems that are devoid of the inherent complexity of their original tumors, which are better captured by in vivo models. Tumor-derived ex vivo models may better mimic the tumor heterogeneity by preserving original TME characteristics, allowing the study of interactions with cancer-associated cells
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