News from Kitos
In a recent perspective article published on Nature Reviews Drug Discovery (link), various members of the European Cell-Based Assays Interest Group summarized limitations of traditional cell-based disease models and discuss how patient-derived cultures, induced pluripotent stem cell (iPSC) technology and 3D co-cultures, complemented by single-cell imaging, microfluidics and gene editing technologies, could improve clinical significance of preclinical drug testing. In this view, limitations of standard cell-line screens and in vivo xenografts contributed to the failure of many drug candidates that did not show clinical efficacy:
The design of new cell-based models should promote a more physiologically relevant environment and recapitulate key features of the disease of interest, as intratumour heterogeneity, poor drug penetrance, host-stroma-tumour interactions, and the cancer stem cell niche:
These new cell-based assays can be complemented by recent technological advances that would exploit their potential:
The authors conclude that these advances are well placed to support a new era of phenotypic drug discovery (generation of hit or lead molecules without any prior knowledge of the target) and to enhance also conventional target-directed drug discovery, if more predictive in vitro models of greater clinical relevance are developed.
We fully agree with the conclusions stated by the authors. Indeed, we developed a cytotoxicity and proliferation assay that take advantage of live-cell imaging to quantify at the same time number of live and dead cells before and after treatment and provide insight on the mechanism of action of drugs. Also, we offer a flexible and reproducible cytotoxicity assay on 3D cultures using a synthetic biomaterial to let reproducible formation of a single spheroid in each well. Despite cell:ECM interaction is missing, it provides useful informations on the role of cell:cell interactions on drug potency and on drug penetrance.
Finally, we would like to emphasize that, despite it is evident that classic cell-based assays can not fully recapitulate clinical efficacy of tested drugs, a big issue on the reproducibility of cancer papers has been raised in the last years. In order to assess the clinical relevance of in vitro studies, it would be first necessary to cross out all the unreproducible results, which is not possible at the moment. If the majority of cancer papers can not be reproduced, as Amgen researchers in 2012 and Baker and Dolgin recently suggested, failure of in vitro studies to translate into the clinical practice is likely to be consequence also of the poor quality behind many of them.
1. Gunjan Sinha; Downfall of Iniparib: A PARP Inhibitor That Doesn’t Inhibit PARP After All. J Natl Cancer Inst 2014; 106 (1): djt447. doi: 10.1093/jnci/djt447
2. Begley CG & Ellis LM. Drug development: Raise standards for preclinical cancer research. Nature 483, 531–533 (29 March 2012) doi:10.1038/483531a
3. Baker M & Dolgin E. Cancer reproducibility project releases first results. Nature 541, 269–270 (19 January 2017) doi:10.1038/541269a