Previously, we briefly commented on the interest generated by the significant study by Georgios Vlachogiannis and co-workers at the Institute of Cancer Research in London, “Patient-derived organoids model treatment response of metastatic gastrointestinal cancers.” This post looks in a bit more detail at this paper which was published in Science on February 23rd, and which supports the evidence that patient-derived organoids are emerging as a relevant and exciting methodology to help develop preclinical diagnostic models for the development of anti-cancer drugs.

Intestinal organoid

Vlachogiannis and co-workers have described a comprehensive piece of work characterising and evaluating patient-derived organoids (PDO) from gastrointestinal cancer patients participating in Phase 1/2 clinical trials.

This paper has  four key aspects:

  • Firstly, that organoids can be established from patients’ metastasised tumour sites, not solely the primary tumour.
  • Secondly, that the patient-derived organoids have genetic, physical and molecular characteristics that are very similar to the patients’ tumour tissue. This opens the door to the use of these PDOs as mimics and models for patient tumours.
  • Thirdly, this study has shown how these PDOs can be used in 3D drug screening assays. The PDOs responded to a library of 55 drugs (used in clinical trials or clinical practice), with a very strong correlation between the replicate assays. The molecular analysis of the PDOs in the screening assays indicate this approach could be used to determine the susceptibility of patients’ tumours to drug treatment.
  • Finally, this paper reported the responses of the PDO panel to four anticancer drugs and compared it with the patients’ responses in the clinical trials. The organoid responses showed a strong overlap with the drug results in the patients: the comparison between the PDOs’ and patients’ response showed 100% sensitivity, 93% specificity, 88% positive prediction and 100% negative prediction.

The authors conclude that this study suggests that “PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs.”

The Today programme on BBC Radio 4 featured a news piece on Friday 23rd February 2018 which is a timely follow on to our previous news piece ‘Organoids – Method of the Year.’ The piece reported by the James Gallagher, the BBC’s Health and Science correspondent, focused on recent research where scientists have been able to predict how cancer patients will respond to therapy by growing miniature versions of their tumours (organoids) in the laboratory.

Biopsies of patients with advanced gastrointestinal cancer were taken and then grown into miniature 3D cancerous organoids in the laboratory. Researchers treated each organoid with the same drug doctors gave to the patient in the clinic. The results showed:

  • If the drug worked in the organoids, it worked 88% of the time in the patient
  • If the drug failed in the organoids, it failed 100% of the time in the patient

Prof David Cunningham, from the Royal Marsden NHS Foundation Trust, where some of the patients were treated, said: “This promising research moves us forward in the field of personalised medicine, and should ultimately lead to smarter, kinder and more effective treatments for patients.”

The research paper detailing this work, “Patient-derived organoids model treatment response of metastatic gastrointestinal cancers,” was published in the February 2018 edition of the journal, Science.

Cellesce has a range of colorectal cancer organoids for applications in drug discovery and for other research applications where large quantities of organoids are required.

In the last few years fundamental cell biology research has moved from studies in two dimensions (2D) looking at cells on flat plastic plates to more comprehensive tools and understanding of how cells work in three dimensions (3D) both singly and in connection to other cells. 3D cell aggregates can be random constructs, or as in the case of organoid culture,  organised multicellular-matrix structures that recapitulate human tissue and organs.
organoids - method of the year

The Nature Methods journal has awarded ‘organoids’ the method of the year

Organoids represent such exciting tools, models and potential for fundamental human biology that the journal Nature Methods has hailed them as their Method of the Year for 2017. In the January 2018 issue (Volume 15, No 1) Nature Methods has focused on the fundamentals and the potential of organoids to be used: as models in mammalian development, as tools to study biological processes; and as models for disease. In addition to research uses, Cellesce is commercially developing organoids as models for drug discovery, further exploiting their recapitulation of human organ characteristics to give in vivo-like drug responses. For readers who are new to the organoid field, the commentary and papers in this special issue of Nature Methods provide a good starting point to understand their basics and their exciting potential for the future.

Cellesce, has formally launched and published the supporting data package for its first range of colorectal organoids. Based on three and a half years of bioprocess development research Cellesce has now successfully grown, reliably expanded and characterised a range of 10 novel organoids. Ethically derived from colorectal cancer patients, these organoids open up exciting new opportunities for further oncology research and compound library screening for drug discovery.

Colorectal organoids

Example images of five of our ten colorectal organoid lines. Confocal images using 20X objective of Cell Insight Cx7. Organoids stained for nuclear (blue) and cytoskeletal (red) markers for imaging. Scale 50μm

Colorectal cancer (CRC), is the development of cancer from the large bowel, which accounts for over 9% of all cancers. It is the third most common cancer worldwide and the fourth most common cause of death, especially in the over 60s. More common in developed countries with an ageing population, the high level of incidence and unmet medical need makes colorectal cancer an active area of research, which the successful development of Cellesce’s organoid technology is enabling, especially in drug discovery.

Cancer organoids are derived from tumours that are grown on in a research lab. Cancer cells divide and cluster to grow into miniature clusters that preserve many of the features of the original tumour, including similar three-dimensional morphology. Most importantly, they show drug responses that are similar to that of the tumours from which they are derived. This offers transformational possibilities for medical research and drug discovery. Organoids can become an inexhaustible supply of miniature tumours for pre-clinical research. The unmet medical need in colorectal cancer is for drug testing systems that better predict patient responses to new compounds including antibodies and small molecule therapeutics.

Cellesce’s initial offering of 10 colorectal cancer organoid lines, have each been DNA profiled and quality assured for consistency, viability after freezing and uniform size. Organoids are frozen and stored in cryovials and are shipped worldwide with instructions for their in vitro research use. Tumour-derived organoids are characterised for their pharmacological responses to a standard set of compounds as part of the quality control process.

Cellesce Founder and Chief Technology Officer, Marianne Ellis said: “These colorectal cancer organoids represent the first product made using our successful and novel bioprocessing expansion technology. We are now moving on to develop normal healthy colorectal organoids to provide a valuable resource from non-cancerous controls for the compound screening, as well as for basic gastrointestinal research.

Cellesce is pleased to announce that it has successfully completed its organoid technology development project. Funded by InnovateUK (the UK’s innovation agency) and NC3Rs (leading the discovery and application of new technologies and approaches to replace, reduce and refine the use of animals for scientific purposes), the project ran from September 2014 to February 2016. Cellesce now has a process for the production of organoids at commercial grade and scale.

Organoids are a powerful new enabling technology in drug discovery and personalised medicine. An organoid is a miniature organ in a gel matrix, grown from stem cells and cultured with tailored growth factors. Because organoids are closer to tissue structure than other available tools, they give more accurate test results. However, up to now, growing organoids has been a labour-intensive manual process, subject to human error, volume constraints, and with significant process variability.

Cellesce has built and validated a scalable process for the expansion of organoids, free from these constraints – and is currently using this process to expand colorectal cancer organoids.

We are currently exploring opportunities to deploy this technology across a range of applications.