Put Your Glasses On, Tumor Pharmacology Goes 3D
by Jon Waterman Smith, August 23, 2016 at 07:00 AM
Attrition rates in oncology drug development are higher than in other disease areas, with almost 95% of compounds showing preclinical activity failing to reach clinical development. This indicates a disconnect between current preclinical models and tumors in patients. CrownBio, in collaboration with the University of Nottingham, has recently developed a system for growing patient-derived tumor cells in 3D. These 3D assays can be used to test anticancer agents ex vivo, and they have shown a higher predictive power compared to current 2D in vitro models.
Cells that make up tissues follow complex and dynamic 3D arrangements, which are important for their physiology. The 3D architecture of a cell influences its ability to respond to external stimuli and to activate an appropriate response. Cancer cells (much like their normal counterparts) benefit from such 3D interactions with each other and with the surrounding extracellular matrix by establishing a unique growing niche, the tumor microenvironment (TME).
Cell lines grown in 2D in vitro culture or in vivo as subcutaneous tumors, are the most broadly used model, thanks to their wide availability and because they are relatively easy to work with. However the question of how well they reflect corresponding patient tumors has become more pressing, with reports of a lack of predictive power for these models. Tumor cells in 2D in vitro cultures have adapted to survive on flat plastic surfaces and have changed some of their original features.
Xenografts produced by subcutaneous implantation of cancer cells in preclinical models typically result in rapidly growing, undifferentiated tumors, which lack the architecture and biological phenotype of the tumors they are meant to represent.
Some important tumor features, e.g. specific gene expression signatures from patient tumors influencing drug sensitivity or resistance, are not always conserved in 2D cell culture or cell line derived xenografts.
Finally, the relationship of tumor cells with their TME, which is known to have a profound effect on drug efficacy, is not conserved in 2D cell cultures or in cell line derived xenografts, further suggesting that models that better capture the reality of tumor biology in situ are necessary to test drug efficacy, specially for new agents that target specific tumor molecular characteristics.
Can We Build 3D Tumors in the Lab?
In a recently published paper, researchers from the University of Nottingham in collaboration with CrownBio devised a system to grow in 3D tumor cells isolated from patient-derived xenograft (PDX) models, the most predictive preclinical models for in vivo pharmacology studies.
PDX models maintain all the original tumor characteristics and have been shown to respond to treatment similarly to patients in the clinic.
The 3D tumor growth assay (3D TGA) uses freshly isolated, fresh frozen, or primary cells derived from PDX tumors, which are grown on a scaffold structure with a very similar composition to the one found in vivo. Tumor cells are also supplemented with patient-derived cancer-associated fibroblasts (CAF), a cell type found in the TME.
The study showed that a wide range of solid tumors can be grown in 3D and that new anticancer compounds can be tested in 3D TGAs to assess their activity. Within the 3D TGA, the team was able to reproduce ex vivo mechanisms of drug resistance previously observed in vivo and, most importantly, were able to increase resistance in the presence of patient-derived CAFs for many agents. This produces a highly relevant assay for drug testing, that takes in to accountthe effect of the TME.
The study also showed that agents commonly used in the clinic had similar responses in the 3D ex vivo and patient-matched in vivo models, validating the 3D TGA as a high-throughput screen for close-to-patient tumors.
CrownBio are committed to furthering preclinical oncology research through the development of more predictive models and assays such as the 3D TGA. The 3D TGA complements other 3D assays that CrownBio already have available for anticancer agent evaluation and development.
Contact us today to receive a copy of our 3D Cell Culture Platform FactSheet and learn more about CrownBio’s 3D TGA and our range of 3D models and capabilities for in vitro and ex vivo testing of anticancer agents.