Advanced Development of Primary Pancreatic Organoid Tumor Models for High-Throughput Phenotypic Drug Screening.

Traditional high-throughput drug screening in oncology routinely relies on two-dimensional (2D) cell models, which inadequately recapitulate the physiologic context of cancer. Three-dimensional (3D) cell models are thought to better mimic the complexity of in vivo tumors. Numerous methods to culture 3D organoids have been described, but most are nonhomogeneous and expensive, and hence impractical for high-throughput screening (HTS) purposes. Here we describe an HTS-compatible method that enables 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 bioprinting technology incorporating magnetic force. We validated this homogeneous 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. This technology was tested for its compatibility with HTS automation by completing a cytotoxicity pilot screen of ~3300 approved drugs. To highlight the benefits of the 3D format, we performed this pilot screen in parallel in both the 2D and 3D assays. These data indicate that this technique can be readily applied to support large-scale drug screening relying on clinically relevant, ex vivo 3D tumor models directly harvested from patients, an important milestone toward personalized medicine

The Scripps Molecular Screening Center and Translational Research Institute

The Scripps Research Molecular Screening Center (SRMSC) was founded in 2004 and comprises more than $22 million of specialized automation. As part of the Translational Research Institute (TRI), it comprises early drug discovery labs and medicinal chemistry. Together with Scripps Research at the La Jolla, California, campus, this represents one of the most competitive academic industrial screening centers worldwide. The SRMSC uses automated platforms, one a screening cell and the other a cherry-picking platform. Matched technologies are available throughout Scripps to allow scientists to develop assays and prepare them for automated screening. The library comprises more than 1 million drug-like compounds, including a proprietary collection of >665,000 molecules. Internal chemistry has included similar to 40,000 unique compounds that are not found elsewhere. These collections are screened against a myriad of disease targets, including cell-based and biochemical assays that are provided by Scripps faculty or from global investigators. Scripps has proven competence in all detection formats, including high-content analysis, fluorescence, bioluminescence resonance energy transfer (BRET), time-resolved fluorescence resonance energy transfer (TR-FRET), fluorescence polarization (FP), luminescence, absorbance, AlphaScreen, and Ca++ signaling. These technologies are applied to NIH-derived collaborations as well as biotech and pharma initiatives. The SRMSC and TRI are recognized for discovering multiple leads, including Ozanimod