3D cultures of heterogenous cells that function in a similar way to an organ are referred to as organoids. There has been an explosion of papers on this technology in the past few years, along with organoids being named as ‘method of the year’ in 2017 by Nature Methods. However, despite all this hype, organoids are not yet commonly used in drug discovery and development. We thought we’d take a deeper look into the literature surrounding organoids in cancer research to better understand whether this upcoming technology could be an invaluable tool for oncology researchers.
In this blog post, we’ll emphasise some of the exciting areas in which organoid use is emerging for drug development, such as personalised therapy, immuno-oncology and genetic editing.
1. Developing patient avatars for personalised medicine
Patient tumour tissue samples obtained from biobanks or through surgery could be used to create patient-derived organoids (PDOs). These can be generated quickly from a small sample of cells, and cultured long-term without genetic alteration from the original tumour. In fact, several studies have reiterated this lack of genetic drift by showing that PDOs behave in a predictable way when cultured with drugs targeting specific pathways.
So, what does this mean for researchers? Perhaps one of the most interesting applications of PDOs is the potential they offer for designing personalised therapies. For example, PDOs could be created for a particular patient to screen the effectiveness of different therapies in the clinic. But, as well as this, PDOs could have a place for creating targeted therapies during drug development. Since PDOs can be genetically characterised, the efficacy of drugs targeting particular pathways can be assessed to create therapies for certain groups of patients harbouring specific mutations in these pathways. This was shown by a team of researchers who classified specific mutations in PLC-derived organoids leading to the discovery of the novel ERK inhibitor SCH772984. In addition to this, PDOs may also help to uncover possible resistance mechanisms – for example, PDOs with a particular mutation or combination of mutations could be used to show which groups of patients may not respond to a given treatment, preventing unexpected (not to mention costly) failures later in clinical trials.
2. Cutting the time to create genetically engineered models
An obvious answer springs to mind when researchers want to incorporate specific mutations into their cancer models: use a genetically engineered mouse model (GEMM). Unfortunately though, these models can be very expensive and time consuming to create. Organoids coupled with CRISPR Cas-9 technology, however, could offer a much cheaper and faster alternative to GEMMs. Specific genes can be easily inserted or deleted within an organoid, giving researchers even more freedom to create a model with the genetic profile required for testing a mutation-specific drug.
Combining organoids with CRISPR-Cas-9 technology could also help pinpoint key players in cancer progression and identify new targets by observing the effects of gene knockout experiments. To highlight an example, a study looked at knocking out 4 genes in intestinal organoids (APC, P53, KRAS and SMAD4). These genes were chosen as they are commonly mutated in colorectal cancers, but interestingly, in this study knock-out of just APC and P53 was enough to cause aneuploidy, suggesting that these are the most instrumental in tumour progression.
3. Recreating the human immune system in vitro
The rise of immunotherapies within the oncology field has revolutionised treatment by using a patient’s own immune system to help fight cancer, but it has also brought with it some challenges for preclinical researchers. The trusted PDX models have little use in this area due to the required immunosuppression in mice. This has been partly overcome with humanised and syngeneic mouse models, but these are still not able to accurately recapitulate the human immune system.
Organoid models could provide pharma and biotechs with another means for investigating cancer immunotherapies. The co-culturing of immune cells with organoids has shown some initial success in incorporating part of the immune system into a preclinical model. In a recent study, co-culture of colon cancer organoids and peripheral blood immune cells caused reduction in organoid size - an indication of the immune cells attacking the tumour.
Using this technique, the efficacy of immunotherapeutic agents can be investigated, along with deepening our understanding of immuno-oncology. In the previously mentioned study, the researchers were also able to identify a resistance mechanism employed by the cancer cells to evade the immune system, leading to the identification of NKG2A as a possible antibody target.
We hope this blog has given you a taster for some of the innovative ways that organoids could become useful tools for enhancing your preclinical cancer research. Arguably, the most ground-breaking of these is using PDOs to study the effect of tumour heterogeneity on drug efficacy, as this is a step towards creating more personalised therapies and evading drug resistance. Although some of these modelling technologies are in the early phase, organoid research is rapidly taking off, with the potential for organoids to soon be used more routinely in drug discovery and development.
Want to learn more about how organoids could be incorporated into your drug development programme?
Image credit: 'Confocal immunofluorescence image of intestinal organoid' by Denise Serra, University of Basel by snsf_scientific_image_competition is licensed under CC BY-NC-ND 2.0