HTS Method Based on 3D Tumor Organoid Cultures

A drug development team has described a high-throughput screening (HTS)-compatible method – based on three-dimensional (3D) tumor organoids – for evaluating multiple chemical compounds for potential chemotherapeutic drug candidates.

Traditional high-throughput drug screening in cancer research routinely relies on two-dimensional cell models, which inadequately recapitulate the physiologic context of cancer. Three-dimensional cell models are thought to better mimic the complexity of in vivo tumors. Numerous methods to culture three-dimensional organoids have been described, but most are nonhomogeneous and expensive, and hence impractical for high-throughput screening (HTS) purposes.

Investigators at the Scripps Research Institute (Jupiter, FL, USA) sought to develop an improved screening method based on three-dimensional organoids. To this end, the described in the April 19, 2018, online edition of the journal SLAS Discovery an HTS-compatible method that enabled the consistent production of organoids in standard flat-bottom 384- and 1536-well plates by combining the use of a cell-repellent surface with a bio-printing technology incorporating magnetic force.

This novel method combined specialized high-density microtiter plates formulated with an ultra-low attachment surface along with gold nanoparticles (nanoshuttles), which were used to label cancer cells in vitro. Once labeled, a magnet assembled the cells into a three-dimensional spheroid or organoid structure. This three-dimensional structure was retained, and chemical compounds were added to assess their therapeutic efficacy.

The investigators validated this process by evaluating the effects of well-characterized anticancer agents against four patient-derived pancreatic cancer KRAS mutant-associated primary cells, including cancer-associated fibroblasts. The technology was tested for its compatibility with HTS automation by completing a cytotoxicity pilot screen of around 3300 approved drugs.

Data obtained during the study indicated that the technique could be readily applied to support large-scale drug screening relying on clinically relevant, three-dimensional tumor models directly harvested from patients, an important milestone toward personalized medicine.

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