Following our recent Teach me in Ten Talk, we’re looking at how organoid technology is changing the landscape of preclinical drug screening. These FAQs outline the advantages, scalability, and translatability of using organoids for drug screening, offering insights that bridge the gap between laboratory research and clinical application.
1. What are the main advantages of using organoids in drug screening compared to traditional cell lines?
Organoids derived from adult tumor stem cells are cultured in an environment that closely mimics their tissue of origin, keeping them both genetically and morphologically in a primary state. Unlike traditional 2D cell lines, which adapt to growth on plastic, organoids maintain a high degree of similarity to the original tissue, for example when you look at gene expression levels but also when looking at drug responses. This high fidelity makes them excellent models for predicting tumor behavior in a preclinical setting.
2. How does the scalability of organoids benefit high-throughput drug screening?
Advanced organoid culturing methods offer the advantage of increased scalability, allowing for high-throughput screening and the testing of many models simultaneously. This capability is essential for conducting large panel screens efficiently, facilitating the exploration of combination therapies and enhancing the overall speed and scope of preclinical drug testing.
3. What limitations does organoid technology face in preclinical drug screening?
While organoids are powerful tools, their use is primarily limited to epithelial tissues due to their derivation from adult stem cells. This restriction means that non-epithelial tumors, such as hematological cancers, brain tumors and sarcomas cannot be modeled using this technology. Additionally, the lack of a tumor microenvironment (TME) in these cultures could be seen as a limitation, although it also presents opportunities for selectively reconstituting the TME by adding back specific cell types, allowing for tuning of the models exactly to your needs.
4. What are the key differences between patient-derived organoids (PDOs) and patient-derived xenograft-derived organoids (PDXOs)?
PDOs and PDXOs both originate from patient tissues but differ in their direct source of material before organoid establishment. PDOs are directly cultured from patients’ tumors, while PDXOs are derived from tumors that have first been grown in mice (PDX). For PDXOs, this means having a guaranteed associated in vivo model available, enhancing their utility for subsequent in vivo studies. Strict QC measures prevent mouse cell contaminations.
PDOs on the other hand, allow for the cultivation of adjacent non-tumorous tissues, providing unique insights into normal versus tumor cell drug responses. This is a unique feature of organoids when compared to any other preclinical model. To allow for in vivo follow up of PDO models as well, we are building a PDXO biobank, meaning that we are making xenograft models from our PDO models.
5. What are the main advantages of utilizing large-scale screening methods in drug development?
Large-scale screening methods, particularly when utilizing organoid banks (such as in OrganoidXplore™), offer significant advantages in drug development. By allowing the simultaneous testing of many different models (currently up to 50, but the number is steadily growing), our screening platform increases the throughput of drug testing significantly. This facilitates rapid data generation—within approximately six weeks from the start of a project—enabling quick decision-making in the early phases of drug development.
6. How do large-scale screenings contribute to biomarker analysis?
Large-scale screening methods facilitate extensive biomarker analysis by testing a single pharmaceutical compound across multiple organoid models simultaneously. If all models in the panel are fully characterized by WES and RNAseq technologies, this approach allows researchers to observe varying responses across the models, enabling them to correlate specific responses with the presence or absence of certain biomarkers. As a result, it provides valuable insights into the compound's mechanism of action and potential efficacy across different biological settings. This data is crucial for identifying potential patient groups who might benefit most from the compound, thereby supporting personalized medicine initiatives.
7. What role do large-scale screenings play in drug repurposing?
Large-scale screenings assess a drug's effectiveness across a variety of disease models, revealing unexpected patterns and potential new applications. When you're testing your drugs across different indications, you could find patterns in unexpected indications that do actually respond. By testing drugs across diverse organoid models representing different indications, researchers can identify previously unrecognized therapeutic potentials of existing drugs. This method not only extends the commercial life of drugs but also offers quicker routes to treatment for patients with limited options. Currently, our panel offers seven different cancer indications.
8. How are in vivo models selected using large-scale screenings?
In vivo models, which are essential for further preclinical studies, can be effectively selected using data from large-scale screenings. Indeed, we offer matched in vivo models for all PDXO and a proportion of our PDO models present in the panel. You could therefore use an OrganoidXplore screen to select in vivo models for follow up. The larger the panel gets, the bigger the impact becomes. These screenings help in determining the most relevant models based on the initial responses observed in vitro. By correlating in vitro data with potential in vivo outcomes, researchers can prioritize certain in vivo models that are more likely to mimic the biological and pathological conditions of human diseases. This targeted selection enhances the predictive value of preclinical trials and improves the overall efficiency of the drug development pipeline.
9. What impact can large-scale screening methods have on clinical trials?
Large-scale screening methods significantly streamline the drug development pipeline by allowing for the early stratification of patients based on biomarker profiles. This pre-stratification process enables pharmaceutical developers to design clinical trials that are more focused and likely to succeed because they target the right patient groups from the outset. As a result, these screenings not only enhance the probability of clinical success but also reduce the time and cost associated with clinical trials by minimizing the likelihood of trial failures. Ultimately, this leads to more efficient development timelines and potentially more rapid delivery of effective therapies to the market.
10. Can you describe the robustness and reproducibility of your organoid-based assays?
The assays demonstrate high robustness, with Z-factors often averaging around 0.7, indicating excellent assay performance. Control variations are minimal (under 20%), and the repeated inclusion of standard of care treatments allows for consistent comparison across experiments. Techniques have been refined to enhance reproducibility, such as use of lab-automation and batching organoids for repeated measurements, ensuring consistent and reliable results over extended studies. Specifically, we’ve studied consistency in an experiment where we have compared the direct responses over 10 passages, taking the same organoid culture every passage again and again, and testing the same direct response. Here we have found very consistent IC50 data, nicely illustrating that these models in general produce very robust and reproducible drug response data.
11. To wrap up, could you once more summarize which services Crown Bioscience offer to address the topic of large-scale organoid screening?
Crown offers OrganoidXplore™, our advanced platform optimized for comprehensive organoid panel screening. This assay-ready service processes up to 50 models in as little as 6 weeks. At the heart of this premier service is an extensive repository of thoroughly characterized PDO and PDXO models including significant mutational profiles. The service has been designed to provide detailed measurements of drug responses in both tumor and normal organoids. Moreover, it facilitates exploration into new cancer indications backed by validated targets and advanced biomarker analysis.
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