There is an urgent and unmet medical need to discover new cancer therapeutics that specifically target diseased cells and minimise adverse side-effects. One of the hurdles to be overcome in identifying new treatments is the availability of a lab-based test system that can accurately predict the efficacy of novel compounds for further clinical development. The use of human-derived tumour organoids is revolutionising the preclinical testing of potential therapeutic compounds. They are a more advanced and biologically relevant model than flat, 2D cultures that are traditionally used in compound screening. Organoids are 3D structures, that can be derived in the lab from normal and tumour tissue. A tiny, cancer biopsy sample for example, can be grown manually, in specialised laboratories, to form multiple copies, which are fully representative of the anatomy and disease pathology of the original tissue. When treated with drugs, the effect on cancer organoids, mirrors the patient response. Their increased selectivity and sensitivity to test compounds better predicts efficacy in the clinic, resulting in fewer false positives or negatives. This increases the quality of compounds that progress to later stages of development and decreases the likelihood that they will fail during toxicity testing or clinical trials - a particularly costly but common occurrence. In order to produce organoids on a larger scale, for more widespread commercial use, Cellesce has developed a unique, patented bioprocess that can produce sufficient cancer organoids for research or small compound screens. The next stage is to scale-up organoid production further for use by pharmaceutical companies to find and select new anti-cancer drugs. For this purpose, a next-generation bioprocess is currently in the final stages of development. This will scale organoid production to 5 times the current capability, with the manufacture of more than 20 million organoids per batch; sufficient for high- throughput screens, early in the cancer drug-development pipeline. In additon, this improvement and scale-up will yield organoids that are cheaper, more reproducible and have lower batch-to-batch variation -- critical features for drug screening. An Innovate UK loan would enable CSE to accelerate the pilot and full-scale testing of this innovative and unique bioprocess, for colorectal, breast, normal and cancer organoids. The output will be fully characterised to show maintenance of the same character as manually grown organoids. They will be validated with known therapeutics to demonstrate efficacy based on their underlying genetic susceptibility and used in a Proof-of-Concept drug screen.

To implement an advanced data analysis pipeline to identify key morphometric signatures from 3D images of screened organoids in drug trials and to classify organoid response for the assessment of therapeutic efficacy for application in the pharmaceutical industry.

Organoids are 3-dimensional (3D) clusters of stem cells that come together and emulate the microenvironment within individual organs, whether that be liver, kidney, heart, gut or other specific organs. Essentially, they can be viewed as miniature, simplified organs. They typically range in size from a few micrometers to five millimeters and there are potentially as many different organoids as there are different tissues and organs in the body. Organoids can also be grown that mimic diseased such as cancer and brain disorders. Such a diverse range of organoids can form by controlling the differentiation of the specific stem cell used, which can be influenced by the cells receiving instructive signals from the 3D extracellular matrix (ECM) and its components, such as bioactive proteins, and the medium the organoids grow in. Organoids hold extraordinary promise: they are a truly disruptive technology capable of completely transforming our understanding of basic biology and also revolutionising the drug discovery process, and its reliance on animal models. That said, growing organoids in the laboratory still requires the use of animal-derived components; in particular, the 3D gel matrix in which organoids grow, which is made from mouse tumours. There are very few suppliers of this matrix and because it is made from animals, each batch is slightly different, it is also unusual in that it is liquid at 4oC but sets to a gel at room temperature, this makes it very difficult for scientists to use and not compatible with robotic systems needed in high throughput drug discovery. Thus, to fully develop the potential of organoids in their capacity to reduce the need for use of animals in research, it is essential that a replacement for this type of 3D matrix is obtained, which is not derived from animals. The aim of this project is to develop a new, fully synthetic (non-animal derived) 3D gel matrix which is optimised for the growth of organoids and can be used in the future for industrial-scale organoid production to drive forwards biomedical research, drug discovery and development of new therapeutics. This will be achieved by combining the proprietary synthetic matrix from Manchester BIOGEL with the optimised bioactive cell signalling growth factor proteins from Qkine to create a wholly synthetic hydrogel that recreates the ideal growth environment for the organoids. Cellesce, a specialist organoid company will help tailor the synthetic hydrogels for different organoid types and downstream applications to maximise the impact on science and the commercial potential of the combined technology.

no public description

To develop novel, real-time, cell ‘happiness’ assays to allow optimisation of the growth of patient samples in 3D mini organ-like cultures. These 'organoids' can be used in drug discovery and genetics research.

"There is an urgent and unmet medical need to discover and develop new disease-modifying breast cancer therapeutics that specifically target diseased cells and minimise adverse side-effects. One of the hurdles to be overcome in identifying new treatments is the availability of a test system that accurately predicts the efficacy of novel compounds for further development in the clinic. The use of tumour organoids will potentially revolutionise the pre-clinical testing of novel therapeutic compounds. Organoids are fully representative, three-dimensional miniature versions of the patient tumour tissue from which they are derived. Donated tissue (given with full patient consent and ethical approval) is processed in the lab to grow into multicellular structures that recreate the anatomy and disease pathology of the original tumour. They are grown in 3D in a dish rather than in an animal and can be expanded in number over a few weeks. These organoids can then be used in drug screening, potentially enabling the determination of targeted therapies for individual patients. Multiple organoid lines representing many different forms of breast cancer can be used in a more general screen for novel treatments, or to test novel combinations of drugs and treatment regimens. Until recently, organoids could only be grown and expanded manually on a small scale, for academic research, limiting their wide-spread commercial use. However, recent advances in bioprocessing technology made by Cellesce, a biotechnology company resulting from a collaboration between scientists from Bath and Cardiff Universities, have enabled the expansion of organoids on a commercial scale. The proprietary method involves seeding established cancer organoid lines into a bioreactor under carefully controlled conditions, to encourage optimal growth and yield. The resulting organoids are subject to rigorous quality control to prove their suitability for use in large scale assays by both commercial and academic institutions. Presently, Cellesce specialises in human-derived colorectal cancer organoids, based on a set of tumour organoid lines generated by, and licensed from, Cardiff University. Published research has shown that human breast tumour organoid lines can similarly be established from patient breast tumour tissue. Combining Cardiff University's research expertise in mammary and organoid biology and Cellesce's proprietary technology and experience, we believe that the large -scale bioprocessing of patient-derived breast tumour organoids will be possible. These organoids will then be made available for the pharmaceutical industry, contract research organisations (CROs) and academic institutions worldwide."

Organoid culture is a new technique that, unlike the use of cell lines, maintains tumour properties in the lab. Organoid cultures should improve the rate at which new drugs are discovered since they should lower the number of ineffective drugs that make their way through animal testing; this will directly lead to new, more effective drugs plus reductions in animal usage in early-stage testing. Realising the potential of organoids in these roles is currently limited by the small numbers of organoids that can be grown in the lab and the expansion of organoid growth is a bottleneck in wider progress, i.e. the ability to supply organoids to pharmaceutical company customers. Therefore the aim of this new collaboration is to develop a bioreactor and accompanying bioprocess to scale up organoid culture. 3D cultures have been developed from a number of different tumour types, however we have chosen to focus initially on colorectal cancer. This particular tumour type is the third biggest cause of cancer morality within the U.K. with approximately 5,000 new cases per year in Wales alone. Ultimately we aim to expand this platform to other tumour types.