In the realm of oncology research, the utilization of three-dimensional (3D) cell models has recently taken center stage, signaling a paradigm shift from traditional two-dimensional (2D) cultures. The high throughput 3D drug screening protocol for patient-derived melanoma and renal cell carcinoma, highlighted in the latest publication from SLAS Discovery, encapsulates this scientific advancement and represents a significant culmination of research conducted by the High-Throughput Molecular Screening Center at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology.

Published on January 11, 2024, with DOI: 10.1016/j.slasd.2024.01.002, the groundbreaking research delineates an ultrahigh throughput screening method for evaluating drug responses using patient-derived 3D organoids. These organoids more accurately imitate the in vivo conditions of tumor microenvironments compared to the flat landscapes of 2D cultures. The comprehensive article provides evidence of the protocol’s effectiveness and discusses its implications for the future of personalized medicine and cancer treatment.

The Need for High Throughput Screening (HTS) in 3D Models

Cancer research has long relied on 2D cell cultures to test the efficacy of therapeutic drugs. However, limitations inherent in these models, such as lack of tissue-specific architecture and cell-to-cell interactions, have led to discrepancies between in vitro effectiveness and actual clinical outcomes. Recognizing the potential of 3D cell cultures to bridge this gap, researchers at the High-Throughput Molecular Screening Center, led by the team of Ortiz Jordan Luis M, Vega Virneliz Fernández VF, and others, embarked on this novel investigative journey.

Patient-Derived Organoids: A Closer Look at Tumor Physiology

The study’s focus on melanoma and renal cell carcinoma (RCC) — two types of cancer with notably high mortality rates — demonstrates the protocol’s relevance and urgency. By utilizing patient-derived primary tumors and their accompanying cancer-associated fibroblasts, the team was able to create 3D organoids that more closely represent the complexity of living tissues.

The organoids were subjected to the National Cancer Institute’s (NCI) library of Food and Drug Administration (FDA) approved oncologic drugs, which allowed the team to scrutinize the heterogeneity in drug responses rooted in genetic variation. Remarkably, this response did not significantly fluctuate based on whether the cells were cultured in a matrix or scaffold-free environments, emphasizing the genetic predisposition over extracellular influences.

Innovations in Drug Screening: 3D Versus 2D

The pivotal findings presented by the research team showcase the enhanced capabilities of 3D cell cultures in drug response profiling. They highlight the disparities in drug responses when comparing 2D versus 3D cultured cancer cells, reinforcing the need for screening protocols that incorporate the third dimension.

Autologous patient-derived cancer-associated fibroblasts were factored into the study to consider the tumor-stroma interactions, which are crucial in understanding drug penetration and resistance mechanisms. The outcome of this comprehensive approach facilitates a sharper lens for identifying potentially efficacious cancer therapies, which paves the way for off-label drug use and repurposing.

The Methodological Backbone of HTS in 3D Cultures

The elaboration of the procedures used in the SLAS Discovery article is of paramount significance, as it provides the scientific community with a viable template for 3D HTS. From sample preparation to data acquisition, each step is meticulously detailed to ensure that the reproducibility and reliability of the results are maintained when adopted by other research centers.

Keywords

1. High Throughput 3D Drug Screening
2. Patient-Derived Organoids Cancer
3. Melanoma Renal Cell Carcinoma Research
4. 3D Models in Oncology HTS
5. Personalized Medicine Cancer Treatment

The Implications and Future Horizons of HTS 3D Screening
By leveraging high throughput screening with patient-derived 3D models, this research stands to revolutionize personalized oncology offerings. It creates an informed path to assess the viability of myriad drugs, potentially allowing clinicians to design tailored treatment regimens that are more effective and less toxic.

Moreover, the platform described in the study presents an expansive opportunity to test other cancer types, moving beyond melanoma and RCC. Researchers could employ this protocol for HTS of various tumor models, expediting the discovery and optimization of precision therapies in oncology.

Conclusion

In conclusion, the novel approach set forth in the January 2024 issue of SLAS Discovery is a testament to the persistent quest for innovation in the fight against cancer. The meticulous design and execution of the high throughput 3D drug screening protocol exemplify the potential of patient-derived 3D organoid models in evaluating therapeutic responses. As the scientific community moves forward, such pioneering work will continue to guide the path towards more effective and personalized treatments for cancer patients worldwide.

References

1. Ortiz Jordan Luis M, Vega Virneliz Fernández VF, Shumate Justin J, et al. Protocol for high throughput 3D drug screening of patient derived melanoma and renal cell carcinoma. SLAS Discovery : Advancing Life Sciences R & D. 2024;S2472-5552(24)00002-9. doi:10.1016/j.slasd.2024.01.002.
2. Langhans, S. A. (2018). Three-Dimensional in Vitro Cell Culture Models in Drug Discovery and Drug Repositioning. Frontiers in Pharmacology, 9, 6. doi:10.3389/fphar.2018.00006.
3. Edmondson, R., Broglie, J. J., Adcock, A. F., & Yang, L. (2014). Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay and Drug Development Technologies, 12(4), 207-218. doi:10.1089/adt.2014.573.
4. Weiswald, L. B., Bellet, D., & Dangles-Marie, V. (2015). Spherical cancer models in tumor biology. Neoplasia, 17(1), 1-15. doi:10.1016/j.neo.2014.12.004.
5. Ravi, M., Paramesh, V., Kaviya, S. R., Anuradha, E., & Solomon, F. D. P. (2015). 3D Cell Culture Systems: Advantages and Applications. Journal of Cellular Physiology, 230(1), 16-26. doi:10.1002/jcp.24683.

Declaration of Competing Interest
The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.