TY - JOUR
KW - Antineoplastic Agents
KW - Cell Line, Tumor
KW - Drug Evaluation, Preclinical
KW - Drug Screening Assays, Antitumor
KW - HT29 Cells
KW - HTS
KW - High-Throughput Screening Assays
KW - Humans
KW - organoids
KW - Pancreatic Neoplasms
KW - Precision Medicine
KW - Cancer
KW - organoid
KW - pancreatic
KW - phenotypic
AU - Shurong Hou
AU - Hervé Tiriac
AU - Banu Priya Sridharan
AU - Louis Scampavia
AU - Franck Madoux
AU - Jan Seldin
AU - Glauco R. Souza
AU - Donald Watson
AU - David Tuveson
AU - Timothy P. Spicer
AB - 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.
BT - SLAS discovery: advancing life sciences R & D
DA - 2018-07
DO - 10.1177/2472555218766842
IS - 6
LA - eng
N2 - 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.
PY - 2018
SP - 574
EP - 584
T2 - SLAS discovery: advancing life sciences R & D
TI - Advanced Development of Primary Pancreatic Organoid Tumor Models for High-Throughput Phenotypic Drug Screening
VL - 23
SN - 2472-5560
ER -