We were present at the last HCS conference in Boston and, during these two days of intensive discussions, lots of topics were addressed in HCS and HCA. I summarize below what seems really important for me.
A lot of molecules fail in the process of drug development in a very late stage (more than 50% in pre-clinical step and phase I for safety reasons, and 80 % for efficacy in phase II). Furthermore, there is more and more data showing that there is a huge transitional problem between animal and human studies. During this event, the pharmaceutical industry and academic groups have shown the importance to use phenotypic screening to found new drugs, but with improved relevance of the in vitro models and data analysis as explain, for exemple, by Christophe Antczak from Novartis. They have published a review on this topic : “How Phenotypic Screening Influenced Drug Discovery: Lessons from Five Years of Practice“. Kristin Fabre from AstraZeneca and Matt Wagoner from Takeda Pharmaceuticals have also highlighted the need for better human models for drug research, in order to improve efficacy and safety of molecules during the early steps of drug research. Another review was presented by Kristin Fabre from AstraZeneca, explaining why we need better human models : “Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework.“
To improve relevance of the in vitro models, many presentations during this event were about 3D culture and the involvement of the micro-environment with modification of the extracellular matrix (ECM). As explained by Sophie Lelièvre from Purdue University for cancer research, during the tumoral progression, the ECM is modified with an increase of its density due to collagen production from cancer cells. The density of the extracellular matrix is a hallmark of tumor aggressiveness. During this tumor progression, there is an increase in the heterogeneity of the cells in the different grades, inducing resistance to chemotherapy. To mimic the tumor progression in in vitro models, it is necessary to reproduce this cellular heterogeneity with the modification of the extracellular matrix in 3D culture.
To improve the relevance of cellular models, microfluidics are also more and more used to generate dynamic models and to better mimic in vivo situation. Different presentations about “organ-on-a-chip” systems during this event have shown that this technology is getting more and more advanced. Jonathan Himmelfarb, from the University of Washington, has shown that 3D model including microfluidic devices to mimic human kidney proximal tubule, express higher transporters and metabolic enzymes compared to 2D model on Transwell filters. Finally, this technology has been already transferred from academic labs to the pharmaceutical industry as shown by Kriten Fabre from AstraZeneca. For example, they use microfluidic systems to check the potential inflammation of lipid nanoparticles.
This event was really of great interest to show that all new technologies like 3D culture, bioprinting, microfluidics for cell culture – and deep learning/machine learning and AI for data analysis – are increasingly used and synergistically help to get predictive human models.
- Review from Novartis : http://online.liebertpub.com/doi/10.1089/adt.2017.796
- Review from AstraZeneca : http://dx.doi.org/10.1038/nrd4309