*PDOS are Patient Derived Organoids
February 28th is Rare Disease Day. In leap years, the day is February 29th, the rarest day of the year. “Rare Disease Day is the globally coordinated movement on rare diseases, working towards equity in social opportunity, healthcare and access to diagnosis and therapies for people living with a rare disease.”
What is meant by FAP and MAP?
Familial Adenomatous Polyposis (FAP) and MUTYH-associated polyposis (MAP) are rare, inherited genetic conditions which predispose to a very high risk of bowel cancer. Patients develop multiple adenomatous polyps. These are small growths on the inner lining of the colon (large intestine), and other areas of the intestinal tract.
Polyps can acquire genetic mutations that disrupt the functioning of the normal cell machinery and cause them to grow quickly, in a dysregulated manner. These polyps are on their way to becoming malignant.
The average age for polyps to develop in patients with FAP is the mid-teens, with multiple polyps developing by the age of 35. MAP may be less severe than FAP with fewer polyps developing and later. The diagnosis is made by analysing the genetic code of the patients to look for specific mutations in the DNA that indicate why the instructions for normal cell growth have been corrupted.
Treatment is by preventative colectomy (removal of some, or all the colon) and regular endoscopic examination of the upper intestines. Endoscopy involves the insertion of a long, thin, flexible tube that has a tiny video camera at the end so that clinicians can closely observe the lining of the intestine as the tube is fed through. Further surgery may be required if polyps form in the duodenum (duodenectomy). Very little is known about the causes of duodenal polyps and how this differs from colorectal disease in FAP and MAP. Research into this area is a high priority as there are high economic and quality of life costs associated with both diseases.
The Inherited Tumour Syndromes Research (ITSR) group at Cardiff University has been developing 3D organoid cell models to represent duodenal malignancy in FAP and MAP patients. In a joint project with Cellesce, these models have been developed further, for use in an industrial environment, to facilitate drug discovery.
Organoids are 3D cell structures that are miniaturised versions of the tissue from which they originated. Organoids derived from intestinal biopsy material from FAP and MAP patients, replicate the biology and appearance of duodenal adenomas or of normal tissue, depending on where the biopsy was taken from. They are used as models for research into the causes and effects of the diseases and as a platform for pre-clinical testing of preventative treatments.
The project succeeded in obtaining living duodenal tissues donated by affected patients. Duodenal adenoma and normal 3D organoid lines from the same patients (for comparison), were successfully derived and expanded.
Duodenal adenoma organoids derived from biopsy tissue from a FAP patient
The ideal treatment for FAP and MAP patients would be to correct or neutralise the effects of the faulty instructions in these patients. This would prevent, or at least delay the growth of polyps and therefore disease progression and cause no unwanted side-effects. To date, no suitable drugs have been discovered that fulfil these needs.
Work is ongoing to find novel treatments and to explore the use of existing drugs that have already been approved for clinical use. This is called drug repurposing. Since safety in humans has already been demonstrated, the drug development timeline and the research and development costs are significantly reduced.
An example of this is a drug called guselkumab (Tremfya), that is used in the treatment of plaque psoriasis. It works by blocking inflammatory and immune responses. Janssen Pharmaceuticals (part of Johnson and Johnson) are performing clinical trials using this drug to treat FAP patients. Additional clinical trials involve the repurposing of icosapent ethyl used to prevent heart attacks (GLW Pharma), sirolimus (Emtora Biosciences), used after renal transplants to prevent rejection of the new kidney and the drugs chosen for the study below.
Pilot drug-treatment study
Sulindac (Merck): a non-steroidal anti-inflammatory
Erlotinib (Astellas Pharma U.S.): a tyrosine kinase inhibitor that slows the growth of cancer cells with specific proteins (“EGFR”) on their cell surface.
To show if the effect of these drugs on 3D organoids mirrors the patient response, duodenal adenoma and the corresponding normal 3D organoid lines will be treated with Sulindac and Erlotinib alone and in combination. If successful, this will demonstrate that 3D duodenal adenoma and normal organoids derived from FAP/MAP patients are a suitable platform on which to test novel compounds and drug combinations for patients with these conditions. Findings from such studies may also be relevant to sporadic intestinal cancer therapy.
At Cellesce we have scaled up the expansion and manufacture of FAP/MAP 3D organoid lines using our unique bioprocessing technology. This will enable them to be used in innovative research and in high-throughput screens by pharmaceutical companies to facilitate drug discovery and development.
The charity Bowel Cancer West supported the initial work to derive and culture FAP and MAP 3D organoid models. Further development of the models was jointly supported by Cellesce and the Clinical Innovation Accelerator through Accelerate, a programme part-funded by the European Regional Development Fund.
None of this work could have taken place without the support and hard work of administrative, research and clinical staff in NHS hospitals, Cardiff University and Cellesce. Neither would it have been possible without the generous donation of biopsy tissue from patients with FAP and MAP, for which we extend our thanks.