Spheroids and high-throughput screening: a method for identifying anticancer therapeutics
Researchers at The Scripps Research Institute have successfully demonstrated the use of spheroids – three-dimensional spherical aggregates of cells – in a high-throughput screen for anticancer drugs.
Scientists at The Scripps Research Institute (FL, USA) have developed a method to identify potential anticancer compounds using both high-throughput screening and aggregates of cells, known as spheroids. The study successfully demonstrates the potential use of the three-dimensional ‘ball-like’ structures in high-throughput screens of thousands of compounds.
Spheroids, which are 100–600μm in diameter, are thought to more accurately mimic the conditions of cells in a tumor microenvironment. The cells are grown in a sphere, rather than a single layer on a plate, and consequently they do not all get the same exposure to oxygen and nutrients.
"Until now, most of the research to screen for cancer drugs has used cells that are growing flat on a plate."
"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," commented corresponding author Timothy Spicer, director of Lead Identification Discovery Biology and High Throughput Screening.
"Until now, most of the research to screen for cancer drugs has used cells that are growing flat on a plate," added author Louis Scampavia, director of HTS Chemistry and Technologies. "With these 3-D spheroids, we emulate much more closely what's found in living tissues."
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Research focused on the protein KRAS, a common cancer-driving protein. Mutations in the RAS family genes are seen in one-third of all cancers and up to 90% of pancreatic cancers are found to be driven by mutations to KRAS. However, the protein has proved difficult to target in the past.
"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," remarked co-corresponding author Joseph Kissil, professor in the Department of Molecular Medicine. "The KRAS protein is relatively small, and that's made it hard to attack it directly. But the method of screening that we used in this study allowed us to come at the question in a different way."
By performing a phenotypic screen to identify compounds that might act on the pathway directing cell growth, researchers identified a compound – Proscillaridin A – that was previously not thought to affect KRAS. Although this drug is unlikely to be developed as an anticancer therapeutic, the finding validates the use of spheroids to identify novel drug candidates.
"It's unlikely we would have discovered this connection using standard 2-D methods,"
"We would love to use this research to create a pipeline for new oncology drugs," Spicer concluded. "Many of the most promising compounds may be overlooked with 2-D screening. This study provides direct evidence that screening for drugs using 3-D structures of cancer cells may be more appropriate."
Kota S, Hou S, Guerrant W et al. A novel three-dimensional high-throughput screening approach identifies inducers of a mutant KRAS selective lethal phenotype. Oncogene doi:10.1038/s41388-018-0257-5 (2018); www.eurekalert.org/pub_releases/2018-05/sri-tsh051118.php