scholarly journals High-Content and High-Throughput In Vivo Drug Screening Platforms Using Microfluidics

2019 ◽  
Vol 17 (1) ◽  
pp. 8-13 ◽  
Author(s):  
Adela Ben-Yakar
Keyword(s):  
High Throughput ◽  
Drug Screening

scholarly journals Testing Tuberculosis Drug Efficacy in a Zebrafish High-Throughput Translational Medicine Screen

2014 ◽  
Vol 59 (2) ◽  
pp. 753-762 ◽  
Author(s):  
Anita Ordas ◽  
Robert-Jan Raterink ◽  
Fraser Cunningham ◽  
Hans J. Jansen ◽  
Malgorzata I. Wiweger ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Drug Efficacy ◽  
Drug Uptake ◽  
Spectrometric Analysis ◽  
Major Advance ◽  
Zebrafish Model ◽  
Content Type ◽  
Screening Platform

ABSTRACTThe translational value of zebrafish high-throughput screens can be improved when more knowledge is available on uptake characteristics of potential drugs. We investigated reference antibiotics and 15 preclinical compounds in a translational zebrafish-rodent screening system for tuberculosis. As a major advance, we have developed a new tool for testing drug uptake in the zebrafish model. This is important, because despite the many applications of assessing drug efficacy in zebrafish research, the current methods for measuring uptake using mass spectrometry do not take into account the possible adherence of drugs to the larval surface. Our approach combines nanoliter sampling from the yolk using a microneedle, followed by mass spectrometric analysis. To date, no single physicochemical property has been identified to accurately predict compound uptake; our method offers a great possibility to monitor how any novel compound behaves within the system. We have correlated the uptake data with high-throughput drug-screening data fromMycobacterium marinum-infected zebrafish larvae. As a result, we present an improved zebrafish larva drug-screening platform which offers new insights into drug efficacy and identifies potential false negatives and drugs that are effective in zebrafish and rodents. We demonstrate that this improved zebrafish drug-screening platform can complement conventional models ofin vivoMycobacterium tuberculosis-infected rodent assays. The detailed comparison of two vertebrate systems, fish and rodent, may give more predictive value for efficacy of drugs in humans.

scholarly journals Mutation Profiles in Glioblastoma 3D Oncospheres Modulate Drug Efficacy

2018 ◽  
Vol 24 (1) ◽  
pp. 28-40 ◽  
Author(s):  
Kelli M. Wilson ◽  
Lesley A. Mathews-Griner ◽  
Tara Williamson ◽  
Rajarshi Guha ◽  
Lu Chen ◽  
...  
Keyword(s):  
Cell Lines ◽  
High Throughput ◽  
Drug Screening ◽  
Kinase Inhibitors ◽  
Proteasome Inhibitors ◽  
Drug Efficacy ◽  
Driver Genes ◽  
Human Gbm

Glioblastoma (GBM) is a lethal brain cancer with a median survival time of approximately 15 months following treatment. Common in vitro GBM models for drug screening are adherent and do not recapitulate the features of human GBM in vivo. Here we report the genomic characterization of nine patient-derived, spheroid GBM cell lines that recapitulate human GBM characteristics in orthotopic xenograft models. Genomic sequencing revealed that the spheroid lines contain alterations in GBM driver genes such as PTEN, CDKN2A, and NF1. Two spheroid cell lines, JHH-136 and JHH-520, were utilized in a high-throughput drug screen for cell viability using a 1912-member compound library. Drug mechanisms that were cytotoxic in both cell lines were Hsp90 and proteasome inhibitors. JHH-136 was uniquely sensitive to topoisomerase 1 inhibitors, while JHH-520 was uniquely sensitive to Mek inhibitors. Drug combination screening revealed that PI3 kinase inhibitors combined with Mek or proteasome inhibitors were synergistic. However, animal studies to test these drug combinations in vivo revealed that Mek inhibition alone was superior to the combination treatments. These data show that these GBM spheroid lines are amenable to high-throughput drug screening and that this dataset may deliver promising therapeutic leads for future GBM preclinical studies.

Patient-derived organoids for personalized drug screening in intrahepatic cholangiocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 581-581
Author(s):  
Ricardo J. Antonia ◽  
Kan Toriguchi ◽  
Eveliina Karelehto ◽  
Dania Annuar ◽  
Luika Timmerman ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Intrahepatic Cholangiocarcinoma ◽  
Three Dimensional ◽  
Small Samples ◽  
Patient Specific ◽  
Mtor Inhibition ◽  
Drug Responses

581 Background: Despite standard treatment with gemcitabine and cisplatin, median survival for unresectable Intrahepatic Cholangiocarcinoma (ICC) is < 1 year. Clearly, novel therapeutic strategies are urgently needed. The paucity of targetable mutations in ICC and the as yet unproven benefit of genetically targeted drugs led us to ask whether a reliable clinical benefit may be revealed by patient-specific therapeutic testing in novel models of ICC. Here we describe our ability to establish patient-derived three-dimensional organoid cultures (PDO) that enable individualized identification of active single agents or drug combinations in surrogate models of ICC. Methods: To model patient-specific drug responses, we used the freshly resected ICCs from small samples of single patient tumors to generate PDXs and PDOs, small spheroidal clusters of tumor cells grown in vitro. We have employed a high-throughput drug screening platform using AI-enhanced robotics (Yamaha Motor Corporation) to identify and distribute single, uniformly sized PDOs into 384-well ultra-low adherent plates. This is coupled with a TECAN D300e drug dispenser that rapidly delivers nanoliter volumes of a 34-drug panel, thereby facilitating rapid, reliable drug response analyses. Results: Our data show that PDOs retain characteristic genomic and histological features of the patients’ tumors. Drug responses were specific to each patient tumor, but PDOs from all patients responded to a greater or lesser degree to mTOR inhibition, suggesting that this pathway is important in ICC. The responses of PDO to the mTOR inhibitor Sapanisertib (INK128), was recapitulated in the same patient’s PDX. Further, INK128 was synergistic with gemcitabine in patient 970 PDOs as well as in vivo in PDX also from patient 970. Conclusions: As it is believed that PDX can predict patient responses to drugs, our results suggest that PDO may also predict patient drug responses. The establishment of PDO may allow economical patient-specific, high throughput drug screens that could ultimately inform clinical practice. [Table: see text]

scholarly journals A high-throughput 3D bioprinted cancer cell migration and invasion model with versatile and broad biological applicability

2021 ◽  
Author(s):  
MoonSun Jung ◽  
Joanna Skhinas ◽  
Eric Y Du ◽  
Maria Kristine Tolentino ◽  
Robert Utama ◽  
...  
Keyword(s):  
Cell Migration ◽  
High Throughput ◽  
Drug Screening ◽  
Cancer Biology ◽  
Cell Movement ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Drop On Demand

Understanding the underlying mechanisms of migration and metastasis is a key focus of cancer research. There is an urgent need to develop in vitro 3D tumor models that can mimic physiological cell-cell and cell-extracellular matrix interactions, with high reproducibility and that are suitable for high throughput (HTP) drug screening. Here, we developed a HTP 3D bioprinted migration model using a bespoke drop-on-demand bioprinting platform. This HTP platform coupled with tunable hydrogel systems enables (i) the rapid encapsulation of cancer cells within in vivo tumor mimicking matrices, (ii) in situ and real-time measurement of cell movement, (iii) detailed molecular analysis for the study of mechanisms underlying cell migration and invasion, and (iv) the identification of novel therapeutic options. This work demonstrates that this HTP 3D bioprinted cell migration platform has broad applications across quantitative cell and cancer biology as well as drug screening.

scholarly journals A novel hanging spherical drop system for the generation of cellular spheroids and high throughput combinatorial drug screening

2015 ◽  
Vol 3 (4) ◽  
pp. 581-585 ◽  
Author(s):  
A. I. Neto ◽  
C. R. Correia ◽  
M. B. Oliveira ◽  
M. I. Rial-Hermida ◽  
C. Alvarez-Lorenzo ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Spherical Drop ◽  
Lab On Chip ◽  
Cellular Spheroids ◽  
On Chip ◽  
High Throughput Manner

A novel hanging spherical drop system based on the use of biomimetic superhydrophobic flat substrates allows one to generate arrays of independent spheroid bodies in a high throughput manner, in order to mimic in vivo tumour models on the lab-on-chip scale.

scholarly journals ATRT-22. HIGH-THROUGHPUT DRUG SCREENING OF FDA-APPROVED CANCER DRUGS REVEALS POTENTIAL THERAPEUTIC APPROACHES FOR ATYPICAL TERATOID RHABDOID TUMOUR

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii280-iii280
Author(s):  
Wai Chin Chong ◽  
Nataliya Zhukova ◽  
Paul Wood ◽  
Peter A Downie ◽  
Jason E Cain
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Prolonged Treatment ◽  
Allelic Loss ◽  
Rhabdoid Tumour ◽  
High Throughput Drug Screening ◽  
Atypical Teratoid ◽  
Rhabdoid Tumors

Abstract Atypical teratoid/rhabdoid tumors (ATRT), are the most common brain tumor in children under the age of 1 year with an overall survival of ~17%. Like extracranial rhabdoid tumors, ATRT is exclusively characterized by bi-allelic loss of SMARCB1, a critical subunit of the SWI/SNF chromatin remodeling complex, implicating epigenetic deregulation in the pathogenesis of disease. We have previously shown the ability of the histone deacetylase inhibitor, panobinostat, to mimic SMARCB1-mediated SWI/SNF functions in extracranial rhabdoid tumors to inhibit tumor growth by driving multi-lineage differentiation in vitro and in vivo. Whether this also applies to ATRT is unknown. Using a panel of human-derived ATRT cell lines, representing defined molecular subgroups, we have shown that prolonged treatment with panobinostat at nanomolar concentrations results in markedly reduced clonogenicity, and increased senescence, preceded by increased H3K27 acetylation, decreased H3K27 trimethylation and EZH2 expression. To determine potentially synergistic therapies, we performed high-throughput drug screening of 622 compounds already in advanced clinical trials or FDA-approved for other indications, across our panel of ATRT models and identified 30 common compounds, which decrease cell viability by &gt;50%, with no effect on neural stem cell controls and 12 compounds which demonstrated subgroup specificity, highlighting the necessity to consider therapies in the molecular context. In addition to HDACi, consistent with our panobinostat in vitro findings, inhibitors of CDK, survivin and PI3K were the top hits. In vitro and in vivo validation of these compounds alone, and in combination with panobinostat is ongoing.

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