3D cell aggregates could improve accuracy of drug screening

13 May 2018

14 May 2018

An innovative new screening method using cell aggregates shaped like spheres may lead to the discovery of smarter cancer drugs, a team from the Scripps Research Institute, California, US, has reported. 

The researchers used a technique called confocal microscopy to confirm that the cell lines were forming spheres. Here is the BXPC-3-KRASWT cell line. Image: Kota et al./The Scripps Research Institute

The 3D aggregates, called spheroids, can be used to obtain data from potentially thousands of compounds using high throughput screening (HTS). HTS can quickly identify active compounds and genes in a specific biomolecular pathway using robotics and data processing.

‘Until now, most of the research to screen for cancer drugs has used cells that are growing flat on a plate,’ said Louis Scampavia, Director of HTS Chemistry and Technologies at the institute. ‘With these 3D spheroids, we emulate more closely what’s found in living tissues.’

Current methods use a single layer of cells that grow at the same rate as they all receive the same exposure to oxygen and nutrients.

The spheroids – 100 to 600 microns thick in diameter – spread in a similar way to cancer cells in the body and are therefore more effective in identifying potential cancer drugs, the team hypothesises.

‘What’s important about this research is that we’re able to do studies using a form of cancer cells that is more physiologically relevant and better recapitulates how these cells appear in the body,’ said Timothy Spicer, Director of Lead Identification Discovery Biology and HTS at Scripps Research Florida site.

For this study, the team focused on KRAS – a gene belonging to the RAS family. Mutations in this family of genes are well known to cause a variety of cancers – from lung to colorectal and pancreatic. It is estimated the genes account for one-third of all cancers.

As the KRAS gene has been linked to 90% of pancreatic cancer cases, the team used pancreatic cancer cell lines in this paper.

‘In the past, KRAS has been a very tricky protein to target. People have spent several decades trying, but so far there has been little success,’ said Joseph Kissil, Professor at Scripps Research Medicine.

‘The KRAS protein is relatively small, and that’s made it hard to attack directly. But the method of screening that we used in this study allowed us to come at the question a different way,’ he said.

The method has already successfully identified a compound that affects the KRAS gene that was previously not associated – Proscillaridin A, a known therapeutic of heart disease.

While the team admit that this particular compound is unlikely to be an effective cancer drug, Scampavia says that the discovery validates the use of spheroids in drug screening.

‘It’s unlikely we would have discovered this connection using standard 2D methods,’ he said. 

‘From our perspective, this is a proof-of-principle study. It shows you can look at libraries of drugs that have already been approved for other diseases, and find drugs that may also work for cancer,’ said Kissil. ‘In theory, you could use this screening method for any line of cancer cells, and any mutation you want.’

Although not definitive, the method shows promise. ‘We would love to use this research to create a pipeline for new oncology drugs,’ said Spicer. ‘Many of the most promising compounds may be overlooked with 2D screening.

‘This study provides direct evidence that screening for drugs using 3D structures of cancer cells may be more appropriate.’

DOI: 10.1038/s41388-018-0257-5

By Georgina Hines

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