Comprehensive Organoid Panel Screening with OrganoidXplore

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Tamlyn Oliver: Hi, everyone. Welcome to Biocompares’ Tech Insights podcast, where we speak to scientific experts about new tools and technologies that can help advance your research. I'm Tamlyn Oliver, managing editor of Biocompare. Today's guest is Hester Bange, Associate Director at Crown Bioscience. She's going to talk about improving organoid panel screening. Thanks for joining us today, Hester.

Hester Bange: Thank you, thank you so much for the invite.

Tamlyn: You're welcome. We have a lot of questions, so we're going to jump right in. Let's start by talking about OrganoidXplore. Can you describe the platform and explain why it was developed?

Hester: So, yes, OrganoidXplore is a compound testing service. So we have a pre-selected panel of 50 organoids. And basically the assay setup is we measure viability over an exposure time of five days. So it's an extensive exposure time. And it's really developed to fast-track the drug discovery pipeline. So really to try early patient stratification or indication selections. We can also use it to look for repurposing of drugs or to validate two components of efficacy, but there we also have smaller panels available, with predefined panels really aiming for specific indications such as lung or colon tumor or mutation such as KRAS. But also clients can select their own panels starting from 20 models if they, for example, have a particular interest in an indication or specifically mutational background. And one of the things that really pushed us to develop OrganoidXplore was, a demand for a faster turnaround time. So we are aiming really to deliver the data now within the six weeks of the initiation of the study. This makes it also really, you know, more economical. Our clients get their data faster and for a cheaper price. They have a simple readout, easy to understand, which really makes it nearing the speed of, the data quality that you see in cell line screening but then you can use organoids, which are much nicer models.

Tamlyn: Can you tell us about Crown Biosciences’ unique assay-ready organoid technology and the advantages that it offers over traditional methods used for organoid based research?

Hester: Yeah, sure. It's a good question. So it's really the essential part of how we can push these timelines to the six weeks I just mentioned. It's really based on optimizing the organoids, the preparation of them, that really allows the uncoupling of the production of the organoids, and the drug testing experiments. So, we try to create, large batches, large amount of the organoids, and, then really also helps us to increase the throughput of these experiments. We need to optimize for every model. It really depends on the indication and the morphology. You know, of the model, if they're compact or cystic or grape like structures, how suited they are. I mean, organoids are a great model, but they do really require a lot of expertise to culture. And it is also, very important that you first validate what you actually have in the dish. Learning to do the culturing, learning to work with these models, but also how to do the validation steps really takes a lot of time. These assay-ready organoids, you can use them, readily. And we all have an optimized process for it, meaning we know how to go to them, we know the timelines, we know the densities, etc. And, an important part of it is, of course, you know, also the QC procedures, we have a fully standardized pipeline for this. So we check that every batch of organoids that we use and that's developed into assay-ready organoids is SNP checked, before the experiment, of course, so that we know that it's actually the organoid that we plan to use that we're using in the experiments, but also, for example, for mouse human contamination, if it's but also compared to the primary tumor, so that we know that we still have what we started with initially. And this makes us really fully aware of what we use, what has been used in the experiments. And an additional advantage is that if you have, larger time, planning experiments over larger time, we can already batch some of these assay-ready organoids for, for the clients that we can do the initial experimental, pilot studies with the same batch of organoids that we will then data on and, continue to use in validation studies for this.

Tamlyn: Okay, so you just mentioned validation studies. Can you describe some of the validation studies that you've performed for the OrganoidXplore platform?

Hester: Yeah, of course. The organoid batches itself were validated just like I mentioned earlier. but when we started to make these assay-read organoids, of course, we wanted to compare the responses of them to, freshly cultured, freshly expanded cultures, to make sure that they actually were similar. So we started with a panel of reference compounds. Such as cisplatin. And after drug treatment, we compared the ICI50s. The curve shapes, between the freshly, expanded organoids and and assay-ready organoids, but also just, in the plate. How did they look like? Do the for morphology still match? Do we see any deviations there? And we did that for the viability readouts or for the CTG. but then we also compare this to our high content imaging data. So to see if you used a more complex readout than just, simple ATP readout, could we then observe differences? And apart from this initial when we were setting up the assay-ready organoid technology, we still continue to check for the reproducibility of these batches. So every experiment we have controls in the plate. At the plate we have predefined cutoffs for, for example Cprime coefficient variance and assay window. And over time we create a large database to see that actually, the readout of the experiments, are comparable.

Tamlyn: One of the benefits of the OrganoidXplore platform that I read about was that it supports drug discovery decision making. Can you explain that?

Hester: Definitely. Yeah, sure. Like I mentioned in the beginning, it really helps with this, early-stage stratification. you know, who could, which patient could benefit from, the treatment that's being developed. But I think, you know, also, it can support the bigger picture. We have 95% of the cancer drugs that fail mostly on efficacy and if you can include many preclinical models in the developmental stage, it's really a good indicator for what patients to include in the clinical trials to really get that number down. Already for like simple chemotherapies, for example, like the reference stroke attempts that's been that we, we most often use right now in in OrganoidXplore the response already is quite variable between the models. And this I think really nicely illustrates how functional assays like OrganoidXplore are needed to help and understand, which patients should be included or and will respond in which not. And apart from that, also with the help of our bioinformatics team here at Crown, we are also, able to couple this to the different backgrounds of the organoids. We have genomic data, transcriptomic data available, for in principle, all the organic models that we include in the panel. And also many of these tumor models, tumor organoid models have already emerged in vivo model available at Crown. So it means really quick translation of your data and really providing this really stronger background, moving forward, with the compounds.The setup itself is also quite versatile. We can not only test small molecules, but we also have biologics data such as antibodies, but also ADCs and even your occasional oncolytic virus that we're now testing.

Tamlyn: One final question. What are the options if a researcher wishes to have their compounds tested against a model that isn't included in OrganoidXplore platform, or they require a different readout?

Hester: Final question already? We're going to expand in OrganoidXplore. We expect to reach the 100 models by the end of this year to be a big achievement, I think, for us all. But also the client specific needs or specific, yeah. things you're interested in. We can always see what we can do. We can prioritize high demand models or see where we can look for this flexibility. And we're always very keen to think along actually with the client needs. But also if a model is not included and it cannot be included, like I said before, also, not all models are possible to have this assay-ready, we can always execute the experiments from fresh or in our classical setup. So we have over 650 organoid models available, from patients to choose from. So they're really a big library if the models were not already included in OrganoidXplore. Also, I should say I mentioned, it's, already a bit earlier, apart from the CPG readouts for both for measuring the ATP, we also offer, high content imaging services, and, it's imaging based, so we stain for the nucleus and for the acting cytoskeleton. and then we do image analysis over the entire zstack. So it's we can really recapitulate all the objects that we have in our well, or the old organoids. on the computer and then image analysis, and then we can really say something about not only to morphology, but also the shape of the objects or the amount of nuclei object and really stratify between a cytotoxic or cytostatic effects and especially this is technology. It's useful when testing for ADCs or antibodies because we can perform additional image, analysis to investigate the penetration of these compounds into the objects. and really copying that to the, to the efficacy readout that we get. So we created nicely therapeutic profile of the drug responses.

Tamlyn: Thanks for joining us today and explaining how the OrganoidXplore platform can be used to accelerate cancer drug discovery. For more on OrganoidXplore, please read the related article Routine and Rapid Compound Testing in a Large Panel of Organoids

Hester: Thank you for having me Tamlyn. It was nice to talk about the OrganoidXplore platform

Tamlyn: And thanks so much for listening. For more information on products, technologies, and the latest scientific advancements, please visit Biocompare.com and have a great day!