1. What challenges or limitations can organoids help overcome?
The high predictive value combined with its scalability ensure that organoid technology has the potential to revolutionize the classical drug development process. ±90% of new cancer drugs fail in clinical trials, and at least in part, these high attrition rates can be explained by a limited understanding of which patients will respond, and which patients will not. Drugs are therefore often not tested in the optimal population of patients, causing drugs to fail.
Organoids can help overcome this, by allowing largescale drug- and model testing, aka preclinical trials in a dish. By testing drugs in hundreds of clinically representative and well characterized models we can learn so much about which patients respond, which do not, and how to recognize them. Deepening our understanding of mechanism of action and accompanying biomarkers will make a great difference in the near future.
2. Could you briefly explain what organoids are, why they are so important, and how they differ from traditional cell cultures?
Organoids are advanced 3D cellular structures that we grow in the lab, established from adult stem cells (in case of tumor organoids, from tumor stem cells), and when kept and used in the right conditions and with the right expertise, are clinically translational models that we can use to model drug responses from patient to patient.
In contrast to traditional cell cultures, organoids highly resemble the original patient tumor, and drug responses found in vitro therefore mimic those observed in the clinic. This makes organoids great avatars for drug developmental purposes: we can predict if a drug will be efficacious, how it does so, and in which patients.
3. What does precision medicine mean to you and how are organoids being utilized in precision medicine?
Precision medicine to me is not only about treating each patient with the best drug available to them. It is also about identifying already in the drug development phase who will and who will not benefit from any novel drug when it enters the clinic.
Organoids can play a vital role in that, as they are models that can accurately predict clinical drug responses in a relatively fast and cheap way. By improving the preclinical pipeline, by including large scale ‘preclinical trials’ in organoids and by subsequentially running more targeted clinical trials, by including more patients that actually have a chance of success, organoids can revolutionize the drug development pipeline.
4.What organoid solutions/technologies does Crown Bioscience offer to help with the precision medicine workflow?
As a global CRO in oncology space, we aim to develop models to recapitulate each and every patient in a dish, providing drug developers with a platform that allows fast and accurate understanding of drug responses throughout the patient population. We have built large biobanks of thoroughly characterized models - approximately 1000 models over 22 tumor types – primary, metastatic, recurrent, resistant; and where resistance models are unavailable, we genetically engineer them ourselves.
These models are available for studying cancer biology at any level. Recent developments of assay upscaling now allows therapy testing in hundreds of organoid models in timespans of weeks, instead of months to a year when testing in classic models. Bioinformatic analysis then allows the identification of predictive biomarkers.
Organoids also allow a deep dive into drug mechanisms of action, for example using high content imaging analysis. Organoid cells closely resemble the ones present in the tumor, including growth factor receptor expression levels and recycling, pathway sensitivities, etc. Therefore, they make great tools for understanding how drugs are affecting actual tumor cells. They also are also amenable to complex co-culture setups, where the interaction between tumor cell, the microenvironment and the immune system can be modelled.
5. How do organoids integrate with other tools and systems used in precision medicine?
As a rule of thumb, I would say any technology used to study patient tumor samples can also be used and of value when studying organoids. We generally do a very deep characterization of all our organoid models, including RNAseq, whole exome sequencing and HLA genotyping, and we have started to implement proteomics analysis as well. Using targeted approaches, organoids are amenable for staining, spatial biology, and flow cytometry analysis.
Something where organoids as a preclinical model are unique in is that they are also available for matched normal tissues. This poses great opportunities for example in neoantigen identification and validation, but also in testing for on- and off-target effects, particularly important in antibody discovery pipelines.
6. Where do you see organoid technology in the next 5-10 years?
First off, I think the scale of organoid studies will increase and increase, and study timelines and costs will decrease along. Organoids will increasingly replace 2D cell lines in early drug discovery, even in large-throughput screens, as the increased predictivity will weigh up against the added costs.
The industry is increasingly adopting organoids into their pipelines, and it will become common practice to test drugs on large patient-derived organoid panels, before moving to in vivo studies, or even directly into clinical trials. The FDA Modernization Act, in allowing to move into clinical trials based on sufficient in vitro data, already paved the way for this. Lastly, complex co-culture capabilities will keep increasing over the years, with more cell types and complexity bringing the models closer to understanding every aspect of tumor biology.
Progress Oncology Drug Development with Organoids
