期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 19, 页码 -出版社
MDPI
DOI: 10.3390/ijms221910720
关键词
glioblastoma; organoids; invasion; patient-derived; compound; drug screening; precision medicine
资金
- Translational Research Institute (TRI) [TL1 TR003109, UL1 TR003017]
- National Center for Advancing Translational Sciences of the National Institutes of Health (NIH)
- Winthrop P. Rockefeller Cancer Institute Seeds of Science Grant [UL1 TR003017]
- NIH [CA158275, CA183895]
- NSF [1903357]
- Arkansas Breast Cancer Research Program
- Winthrop P. Rockefeller Cancer Institute Seeds of Science Grant
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1903357] Funding Source: National Science Foundation
This study screened potential GBM therapeutic drugs using patient-derived 3D models, finding that tubulin inhibitor had the best efficacy in U-251 MG cells but showed highly variable results in patient organoids. The efficacy of compounds was found to be closely related to patient tumor heterogeneity, suggesting that such models can be used to evaluate individualized cancer treatment strategies.
Glioblastoma (GBM) is highly resistant to treatment and invasion into the surrounding brain is a cancer hallmark that leads to recurrence despite surgical resection. With the emergence of precision medicine, patient-derived 3D systems are considered potentially robust GBM preclinical models. In this study, we screened a library of 22 anti-invasive compounds (i.e., NF-kB, GSK-3-B, COX-2, and tubulin inhibitors) using glioblastoma U-251 MG cell spheroids. We evaluated toxicity and invasion inhibition using a 3D Matrigel invasion assay. We next selected three compounds that inhibited invasion and screened them in patient-derived glioblastoma organoids (GBOs). We developed a platform using available macros for FIJI/ImageJ to quantify invasion from the outer margin of organoids. Our data demonstrated that a high-throughput invasion screening can be done using both an established cell line and patient-derived 3D model systems. Tubulin inhibitor compounds had the best efficacy with U-251 MG cells, however, in ex vivo patient organoids the results were highly variable. Our results indicate that the efficacy of compounds is highly related to patient intra and inter-tumor heterogeneity. These results indicate that such models can be used to evaluate personal oncology therapeutic strategies.
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