Organoids or ‘mini-organs in a dish’ are one of the most exciting developments of stem cell research in recent years. Defined as three-dimensional (3D) cell structures, organoids form functioning physiological systems that mimic some of the key characteristics of the corresponding organ or tissue in vivo. In preclinical research, organoids can be used to study the effects of novel drugs, to observe tissue development and morphogenesis, and to examine different disease mechanisms.
While preclinical drug development has traditionally used cell lines or animal models to investigate new drugs, organoids are an exciting alternative in many ways. The ultimate aim in preclinical stages is to characterize new compounds and establish their efficacy and safety before they are tested in humans.
However, in oncology, attrition rates for new anticancer agents are higher than in other disease indications. This suggests that there is an immediate need for advanced preclinical models that better translate to humans as early as possible in the drug development process. Patient-derived xenografts (PDX) are one example in which human tumors are engrafted into the mouse model.
Weighing the benefits of cell lines, PDX models, and organoids
In the last decade, the focus has significantly shifted from drug screens using immortalized cell lines to adopting PDX models, which have been proven to be highly predictive and can be used as patient avatars to investigate responses to cancer treatment.
However, PDX models take time to develop and can be costly. As organoids mimic functional human tissues and organs in vitro, such as the stomach, intestine, lung, liver, or breast, they can reflect human reactions to drugs better than traditional in vitro tools and are as predictive as PDX models.
“Cell lines have relatively poor predictability and animals have a disadvantage in terms of cost and high-throughput for compound screening,” says Henry Li, CSO at Crown Bioscience. “But both tools also hold many advantages. For example, PDX models are more reflective of the human original tumor pathophysiology, while in vitro cell lines can be used for high-throughput screening and testing many compounds simultaneously. Organoids, on the other hand, can potentially fill the gap for a robust predictive in vitro model that can be easily scaled up for large scale screens while preserving relevance to the original patient tumor.”
Developing a disruptive new platform for drug development
The use of organoids in preclinical stages has increased greatly. In 2019, the market value was estimated to be around $32M and is expected to rise to $134M in the next decade. In cancer research, organoids are increasingly being adopted to understand tumor biology and to assess responses to treatment as well.
“The greatest advantage of organoids is the fact that we can test loads of different agents on a large number of models simultaneously in a high-throughput fashion,” Li explains. “Certain cell lines might be used for the same purpose, but they don’t recapitulate the original patient tumor morphology, genomic, and transcriptomic profile as faithfully as organoids. Also, isolated primary cells cannot provide a robust testing platform. Organoids are considered a step closer to mimicking a human organ or tissue in a dish. This is why we have seen significant growth in the application of organoids for drug discovery and development.”
To answer the need for more translational in vitro models, CrownBio has entered an exclusive agreement with Hubrecht Organoid Technology (HUB) which allows them to provide preclinical oncology drug discovery services using organoids based on the HUB technology. This includes HUB’s already established biobank of patient-derived organoids (PDO) and their matched healthy tissue-derived organoids, as well as new tumor organoids derived from Crownbio’s PDX models that can be used to expand human tumors. These are referred to as PDX-derived organoids (PDXO).
Matching in vivo and in vitro systems to test drugs
“With PDX and PDXO we now have a matching system to test drugs,” Li explains. “One is in vivo, the other is in vitro. During drug discovery and the preclinical stages of drug development, it is important to evaluate the drug as much as possible so you don’t have to test it as extensively in the clinic. It all comes down to minimizing tests in humans. We want to get as much information on the drug as possible in the preclinical setting, so we need in vitro screening data and an in vivo readout.”
Li explains that matched PDX and PDXO models are derived from the same patient tumor and are proven biologically equivalent. Large libraries of PDXO can be developed by leveraging CrownBio’s expansive collection of well-characterized PDX models, therefore offering a matched in vitro/in vivo platform.
These PDX libraries represent patient diversity and heterogeneity and offer clinically relevant information for preclinical drug discovery. Similar to the corresponding PDXs, PDXOs undergo extensive characterization to verify their identity and to collect data that can be used for biomarker discovery.
PDXO tumor organoids explained
The fundamental science behind the tumor organoids is derived from the research of Hans Clevers group, who were the first to describe protocols for organoid development derived from adult stem cells (ASC). Clevers observed that there were certain in vitro tissue culture conditions in which stem cells could expand and divide indefinitely to form functional tissues or organs that mimic the physiological conditions of the human body.
“When developing PDXO tumor organoids, we take the cancer stem cells found in the PDX and follow certain procedures using the protocols published by Hans Clevers,” Li explains. “Eventually, these stem cells will form the mini-tumor or tumor organoid.”
Taking over the global market with tumor organoids
With the help of its exclusive partnership with HUB and its extensive collection of PDX, CrownBio is working on creating the largest biobank of organoids and providing oncology research services through its new translational in vitro screening platform.
“We have exclusive commercial license rights for applications of the HUB technology to preclinical oncology drug development,” says Li. “Together with our large PDX-derived library of over 3000 PDX models, this gives us a great advantage on the global market. In the near future, we hope to become the main provider in preclinical oncology services based on organoids.”
Do you want to learn more about organoids and the advantages they bring to drug discovery and development? Get in touch with the experts at CrownBio or check out their website and discover all there is to know about PDXO tumor organoids.
Images via CrownBio & Shutterstock.com