Drug Discovery Goes Three-Dimensional: Goodbye to Flat High-Throughput Screening?

Eglen, Richard M.; Randle, David H.

doi:10.1089/adt.2015.647

Cited by 74 publications

(59 citation statements)

References 19 publications

(35 reference statements)

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“…A similar approach tested in human liver organoids yielded promising results indicating that the organoid system was amenable to therapeutic testing [109]. Methods are being developed for drug discovery using high throughput testing in 3D cultures which could be applied to therapeutic testing in patient-derived organoids [110]. Finally, a retrospective study using prostate organoids found that the organoids derived from distinct patients displayed different responses to therapies which correlated with the observed genetics of each patient’s cancer [10], suggesting that therapeutic testing of organoids will have clinical benefit.…”

Section: Using Organoids For Personalized Medicinementioning

confidence: 99%

Modeling Pancreatic Cancer with Organoids

et al. 2016

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Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy for which new treatment and diagnostic approaches are urgently needed. In order for such breakthroughs to be discovered, researchers require systems that accurately model the development and biology of PDA. While cell lines, genetically engineered murine models, and xenografts have all led to valuable clinical insights, organotypic culture models have emerged as tractable systems to recapitulate the complex three-dimensional organization of PDA. Recently, multiple methods for modeling PDA using organoids have been reported. This review aims to summarize these organoid methods in the context of other PDA models. While each model system has unique benefits and drawbacks, ultimately, organoids hold special promise for the development of personalized medicine approaches.

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Section: Using Organoids For Personalized Medicinementioning

confidence: 99%

Modeling Pancreatic Cancer with Organoids

et al. 2016

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“…in situ imaging) to predict which spheroids are pre-organoids, then the early stages of culture could be efficiently engineered, possibly bypassing the initial morphogenesis events, to produce a higher yield of desirable pre-organoids and thus organoids. Such improvement is essential to making organoid platforms tractable for large-scale studies and commercial applications such as pharmacogenomic profiling, selecting hits from drug screens, and optimizing lead compounds (Boehnke et al, 2016;Gordon et al, 2015;Edmondson et al, 2014;Eglen and Randle, 2015). Increasing the efficiency of pre-organoid production increases the predictability of downstream studies and decreases their scale while reducing costs and wasted reagents.…”

Section: Introductionmentioning

confidence: 99%

A process engineering approach to increase organoid yield

et al. 2017

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Temporal manipulation of the in vitro environment and growth factors can direct differentiation of human pluripotent stem cells into organoids -aggregates with multiple tissue-specific cell types and three-dimensional structure mimicking native organs. A mechanistic understanding of early organoid formation is essential for improving the robustness of these methods, which is necessary prior to use in drug development and regenerative medicine. We investigated intestinal organoid emergence, focusing on measurable parameters of hindgut spheroids, the intermediate step between definitive endoderm and mature organoids. We found that 13% of spheroids were pre-organoids that matured into intestinal organoids. Spheroids varied by several structural parameters: cell number, diameter and morphology. Hypothesizing that diameter and the morphological feature of an inner mass were key parameters for spheroid maturation, we sorted spheroids using an automated micropipette aspiration and release system and monitored the cultures for organoid formation. We discovered that populations of spheroids with a diameter greater than 75 μm and an inner mass are enriched 1.5-and 3.8-fold for pre-organoids, respectively, thus providing rational guidelines towards establishing a robust protocol for high quality intestinal organoids.

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“…The ability to capture tumor heterogeneity makes organoids superior to traditional cancer cell lines (13,14). Therefore, organoids can be an excellent tool in the future for ex vivo drug screening to select targeted therapy (15,16). Testing therapeutic agents in preclinical 3D cell cultures may also help reduce unnecessary side-effects and might reduce treatment costs.…”

Section: Discussionmentioning

confidence: 99%

On-site Cytology for Development of Patient-Derived Three-dimensional Organoid Cultures – A Pilot Study

Sailer

Pauli

Merzier

et al. 2017

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Abstract. Background/Aim: Development of patient-derived three-dimensional (3D) organoid cultures is an emerging technique in the field of precision oncology. We aimed to integrate on-site adequacy evaluation using cytology into the tumor organoid development workflow to ensure precise characterization and growth of these cultures. Patients andPersonalized medicine, also referred to as Precision Medicine (PM), is the approach to treat a patient's disease by taking into account the molecular landscape of the individual tumor or disease process. In addition to its role in oncology, PM is also employed in the treatment of other chronic conditions such as autoimmune disorders. In the United States, the Precision Medicine Initiative ® was launched by President Barack Obama in early 2015 in order to facilitate individualized patient care. Recently, the National Institute of Health (NIH) awarded $55 million to enroll one million patients in a multi-institutional precision medicine trial (1).In the field of Precision Oncology, the development of patient-derived 3D tumor organoid cultures is an emerging model that can be a valuable tool for predictive in vitro drug testing (2). Although cell lines have long been established for preclinical drug testing, they do not sufficiently recapitulate the innate tumor heterogeneity and therefore the genomic complexity. Organoid cultures are thus the preferable method for predictive drug testing (3). Organoids are derived from stem cells and are self-organizing and selfrenewing (4). Since organoids maintain the genetic representation of a patient's tumor, they are a readily available source of high-quality DNA and RNA for next generation sequencing (NGS). In order to initiate organoid development, fresh tumor tissue is collected and processed 1569This article is freely accessible online. Organoid development is a time-and cost-intense process. As yet, no cost estimate per organoid development has been published. Organoids are usually propagated in Matrigel Matrix (Corning Inc. USA), which closely resembles extracellular matrix. It provides a scaffold for cells to grow and proliferate (7). Matrigel is a relatively expensive medium priced at approximately $318 per bottle. Costs for technical staff adds to the expenditure for cell culture infrastructure and consumables. Submitting tissue for organoid development "blindly", i.e. without prior characterization, can result in spending money and time propagating benign organoids. Submitting only lesional tissue for further processing is therefore paramount. Rapid on-site evaluation (ROSE) is a common practice in cytopathology that assesses tissue samples for adequacy of material for diagnostic purposes. We have recently shown, that cytological evaluation of organoids within a few weeks into their development can successfully characterize them (8). In the present study, we aimed to integrate on-site cytological evaluation during tissue collection to identify viable tumor for organoid development and guide decision-making on the early fate ...

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Drug Discovery Goes Three-Dimensional: Goodbye to Flat High-Throughput Screening?

Cited by 74 publications

References 19 publications

Modeling Pancreatic Cancer with Organoids

Modeling Pancreatic Cancer with Organoids

A process engineering approach to increase organoid yield

On-site Cytology for Development of Patient-Derived Three-dimensional Organoid Cultures – A Pilot Study

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