cancer: adding a new dimension to drug screening
The average cost of bringing a new drug to market is nearly £2 billion dollars – that’s enough to fund two trips to the moon, or buy the Solomon Islands! Unsurprisingly, anything that could reduce these costs in any way would be gladly welcomed by the pharma and healthcare industries alike, making this a hot topic of research (and debate!).
One way to reduce costs is to improve the efficiency of drug discovery and early pre-clinical screening by using more physiologically relevant drug screening models. To help keep you up-to-date on the latest trends, our new e-book draws upon knowledge from several industry thought leaders to explore how cutting-edge phenotypic screening of 3D cell cultures is being used to identify hit compounds to take forward into later stages of the development process.
Improving the quality of candidate drugs
At its core, drug development is exceedingly expensive because it requires a vast amount of time and resources in order to:
- discover a candidate drug with the potential to treat disease
- assess efficacy and toxicity, both via pre-clinical assays and then human clinical trials
- bring it to market
This is exacerbated by the fact that success rates are often very low, meaning much of this work delivers little or no tangible outcome. In the case of cancer drugs this is even more pronounced, with as few as one in twenty drugs tested in human clinical trials being successful.
Fortunately, pre-clinical models for screening and testing new compounds are improving rapidly and promise to generate data that better reflects how drugs perform in vivo. These advances aim to reduce the rate of failure during clinical trials by improving the quality of hit molecules identified via high content and throughput screening (HTS).
Coming back around to phenotypic screening
The methods employed in drug screening have come full circle in the past few decades: phenotypic screening was side-lined during the second half of the 20th century in the wake of enhanced genomic and molecular knowledge which favored a target-based approach. However, phenotypic screening regained popularity at the start of the 21st century, as the perceived challenges of the approach were overcome partly due to technological advances. This swing has been so pronounced that 37% of the first-in-class drugs approved by the FDA between 1999 and 2008 were discovered as a result of phenotypic screening, compared to only 23% via target-based screening even though the majority of screens performed at this time were target-based.
A need for better models in oncology
While other areas of research were benefiting from the resurgence in phenotypic screening methods, the field of oncology was still facing a challenge: how to combine the need to use fairly complex assays capable of robustly mimicking the nature of tumors in vivo, with the time and cost benefits offered by simpler models compatible with HTS (Table 1).
3D tumor culture screening begins to yield positive results
While adapting 3D cell culture to HTS has been challenging, the potential benefits offered over 2D culture have driven assay development forward:
- cell cultures plates compatible with Society for Biomolecular Screening (SBS) standards are now offered in 96- and 384-well formats
- 3D culture plates (e.g. low attachment, hanging drop, micropatterned) now commercially available
- a number of 3D cell culture analysis tools now exist (e.g. spectrophotometric and high content analysis)
To achieve the throughput required for screening the first challenge is to set up a large number of identical 3D cell cultures, the second challenge is to obtain fast, automated assay readouts of these more complex assays. TTP Labtech’s acumen® Cellista is ideally suited for the rapid (5 minutes/plate) high throughput analysis of tumor spheroids and colonies, without the need to acquire a Z-stack of images.
Staining of tumor spheroids/colonies followed by imaging on acumen Cellista allows the determination of a range of parameters, such as spheroid number, area and volume, and also provides a measure of cell viability following drug treatment.
Combining 3D cell culture methods with high throughput methods to improve drug discovery as part of cancer research programs represents a paradigm shift in how screening is being conducted in modern pharmaceutical labs.