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Simulating tumor complexity: 3D pancreatic tumor spheroid model for improved drug screening
Bano Subia1, Ankit Patel2, Simran Nathwani2
1Zydus Research Centre, Zydus Life Sciences, Ahmedabad, Gujarat, 382210, India. subia.m.bano@zyduslife.com.
Abstract:
Most drug discovery studies use 2D cell cultures and animal models for screening new chemical entities (NCEs), which often leads to suboptimal results due to genetic variations, species differences, or lack of most physiological preclinical models. This is one of the most important reasons behind high rate of failure of drug candidate in the clinic, especially in oncology drug development projects. To address this issue, we developed a 3D pancreatic tumor spheroid model that better mimics the parental tumor architecture. We observed similar drug effects on cellular viability in both 2D cultures and 3D spheroids. However, cellular viability alone is insufficient to predict the translation of efficacy into clinical studies. A 3D multicellular tumor model is essential to comprehensively evaluate drug effects on the tumor microenvironment (TME), angiogenesis, and tumor biomarkers. Our model includes 3D monocellular and multicellular spheroids, which demonstrated a more relevant platform for potency evaluation. We used pancreatic ductal adenocarcinoma cells PANC-1 and PANC04.03 to conduct a comprehensive drug screening and assessed spheroid shrinkage and pre-vascularization. We also evaluated RT-qPCR analysis for gene expression of CSC markers (CD44, SOX2, KRT18), EMT markers (αSMA, vimentin) and the apoptotic marker (Annexin A1) under various conditions. Our findings highlighted the significant differences between 2D and 3D cultures, underscoring the importance of 3D multicellular models for predicting therapeutic markers and enabling comprehensive drug evaluation. In this study, MRTX1133 (a Phase I candidate of KRAS-G12D inhibitor) was used for testing our hypothesis. Treating the spheroids with MRTX1133 revealed enhanced drug response profiles compared to 2D cultures. This study underscores the critical importance of 3D multicellular model in preclinical drug screening and their potential to bridge the gap between in vitro studies and clinical outcomes.
Insights
Developing a 3D pancreatic tumor spheroid model improves preclinical drug screening. This advanced model better predicts therapeutic efficacy by evaluating the tumor microenvironment and biomarkers, unlike traditional 2D cultures.
Area of Science:
- Oncology
- Drug Discovery
- Biotechnology
Background:
- Traditional 2D cell cultures and animal models present limitations in preclinical drug screening due to physiological differences.
- High failure rates in clinical trials, particularly in oncology, stem from inadequate preclinical models that do not reflect human tumor complexity.
Purpose of the Study:
- To develop and validate a 3D pancreatic tumor spheroid model for more accurate preclinical drug evaluation.
- To assess the utility of this 3D model in predicting therapeutic responses, tumor microenvironment interactions, and biomarker expression.
Main Methods:
- Established 3D monocellular and multicellular pancreatic tumor spheroids using PANC-1 and PANC04.03 cell lines.
- Evaluated drug effects on cellular viability, spheroid shrinkage, and pre-vascularization.
- Assessed gene expression of cancer stem cell (CSC), epithelial-mesenchymal transition (EMT), and apoptotic markers via RT-qPCR.
Main Results:
- 3D spheroids demonstrated a more relevant platform for drug potency evaluation compared to 2D cultures.
- Significant differences in drug response and biomarker expression were observed between 2D and 3D models.
- The KRAS-G12D inhibitor MRTX1133 showed enhanced drug response profiles in 3D spheroids compared to 2D cultures.
Conclusions:
- 3D multicellular tumor models are crucial for comprehensive drug evaluation, offering a more physiologically relevant platform than 2D cultures.
- This 3D model has the potential to bridge the gap between in vitro preclinical studies and clinical outcomes in oncology drug development.
