Grants to a total of £220,000 were awarded in 2015 for the following projects and some of them have been completed.
Liquid biopsy for prostate cancer
Every year over 9,000 patients with prostate cancer undergo radiotherapy. Although this is generally a very good way of halting the disease, like all treatments it can sometimes fail. In such cases some patients may be suitable for additional treatment to remove the tumour, using either high-intensity focused ultrasound that ‘heats’ or cryotherapy that ‘freezes’. This project aims to establish which patients could benefit from one of these treatments by measuring changes in the levels of cell free DNA (cfDNA) and circulating tumour cells (CTCs) in the blood.
Mr Hashim Ahmed, MRC Clinician Scientist in Uro-oncology, with Professor Mark Emberton, Mr. Taimar Shah, Dr Mark Linch. UCL Hospitals.
In this experiment, Dr Rueda has established the best technique for the extraction and identification of cell free DNA (cfDNA) from the blood of patients with relapsed prostate cancer. There was no correlation between the cfDNA and the Gleason score of the cancer. Similarly, there was no change after salvage treatment and no correlation with the tumour burden. This technique is useful, but more work will have to done to identify specific markers of prostate cancer.
Investigating molecular markers in primary urethral and penile cancers
These cancers are rare but spread very quickly, resulting in a poor survival rate for the patients. UCLH has been designated as a referral centre so that cases are concentrated in a single unit. This improves patient care and allows research with the largest possible numbers.
The researchers are studying various protein markers known to be associated with cancer growth, spread and invasion, in order to examine where drugs and other therapies may be of help in improving outcomes.
Mr Varun Sahdev, Mr Asif Muneer, Dr Alex Freeman. Departments of Urology and Pathology, UCLH.
Work to date: A comprehensive database has been developed to identify all the relevant samples held in the pathology department and off site for affected men. Their pathology slides have been retrieved and reviewed to identify the tumour areas of interest.
The next step is to obtain the original tissue blocks that are in remote storage, so that appropriate fine sections can be cut for the identification of biomarkers and comparison between the two diseases. It is hoped that common markers will be found and that a common treatment strategy can be developed for them. The preparation and analysis of the pathology specimens will be funded.
Equipment for the Centre for Nephrology
A contribution has been made towards provision of a ‘state of the art’ confocal microscope and multiphoton microscope equipment for the imaging required in a wide range of biomedical research projects in the Centre for Nephrology.
Professor Robert Kleta and other researchers in the Centre for Nephrology.
This has been purchased and is in use
CMOS camera for selective plane illumination microscopy
CLARITY is a novel and exciting technique for 3D imaging of the form and structure of the kidney and gut. It requires a special camera and the Trust has agreed to purchase one to enable the establishment of the technique in the Centre for Nephrology.
Dr Anselm Zdebik, Dr Joanna Marks, Dr Steven Walsh, Dr Felice Leung.
Biomarker discovery with gene chip analysis cell model systems for renal Fanconi syndromes
The kidney contains cells that are important in the reabsorption of substances from the urine back into the blood. These specialised ‘proximal tubular cells’ need fatty acids as their source of energy. A malfunction of these cells results in a disorder called Fanconi renotubular syndrome (FRTS). The team has shown that in patients with a specific form of the disorder fatty acids cannot be used properly and the resulting deficiency in energy production is the cause of the disease. Impaired energy also appears to be central to other common kidney diseases and it is hoped that this research will provide explanations of other conditions too.
Dr Enriko Klootwijk, Dr Horia Stanescu, Professor Robert Kleta.
This study has been successfully completed. A very large amount of data was collected. Sophisticated computational tools such as STRING and DAVID were used for analysis. As expected, it was found that fatty acid-related energy production was affected in FRTS. It was confirmed that this was the main source of energy for the proximal tubular cells. Novel fatty acid biomarkers were identified which will be investigated in a future project. Incidentally, analysis of the ‘big-data’ sets revealed novel defects in expression amounts of genes in FRTS that were not directly related to fatty acid regulated energy production – material for future work.
A publication is in preparation. The data are forming the basis for a grant application to the Wellcome Foundation or the MRC to look more closely at the novel biomarkers and their potential impact in common diseases such as acute kidney injury and chronic kidney disease.
The Trust is delighted with this outcome. Funding of ‘seed’ projects which lead to grant applications to more major donors is a key part of our work. This is very much the case here. Furthermore, as so often, the team made other important discoveries which are of value in diseases outside FRTS.
Metabolic detection of kidney cancer
This cancer kills over 4,000 people each year in the UK, but if detected early it is treatable by surgical removal. Kidney cancers are often caused by a block within the cancer cell of the process by which sugars are broken down to release energy. The project will measure the urinary levels of compounds produced when this block occurs and find out whether it can be used to detect the cancer at an early stage. This will be done by studying a group of patients known to be at high risk of the disease who are routinely having surveillance kidney scans. This project is a collaboration between the genetics skills in nephrology and the oncology skills in urology.
Dr Daniel Gale, Mr Michael Aitcheson. Centre for Nephrology and Department of Urology.
Sanger sequencing in idiopathic membranous nephropathy (iMN)
This organ specific autoimmune disease is a major cause of the nephrotic syndrome and renal failure in patients in the UK. It is proposed to sequence the gene locus for the M-type Phospholipase A2 Receptor (PLA2R), as antibodies to it are able to cause disease and are present in 60-70% of patients with iMN. More than one form of the gene has been shown by Dr Stanescu to confer a significantly increased risk of developing the disease. Fully sequencing the position of this gene on a chromosome could provide understanding of the likely effects that different forms of the gene have on the structure of the PLA2 receptor and the consequences that this has on its ability to produce an immune response. The Trust is funding the consumables for this project.
Dr Horia Stanescu, Dr Steven Walsh, Dr Sanjana Gupta.
This study has now been completed. The genetic code of the whole PLA2R1 gene in people with membranous nephropathy was fully read in 334 British European people to identify which changes were taking place that were different to healthy European control subjects. A change (more commonly called a variant) in the DNA code was present in 98% of people with membranous nephropathy. This compared to 17% in the controls. This difference is highly significant and supports the view that the variant is contributing to, or causing, membranous nephropathy. It is found in the region that does not contain the blueprint for the actual building blocks but in one that is important in controlling the switch to start making the protein from the building blocks.
Detection of lymph node metastases in penile cancer: a comparison to imaging and traditional surgical dissection
Cancer of the penis is another rare cancer for which UCLH has been designated as the referral centre. The number of cases being referred to UCLH now makes it possible to begin meaningful research on this devastating disease. The most important clinical prognostic factor is whether or not the lymph nodes in the groin which are the first site of spread, are involved. At present this can only be discovered by removing the nodes which often causes serious morbidity. This project will evaluate the use of epigenetic biomarkers in the blood to see if they can be used to diagnose the lymph node spread. The result of the blood tests will be compared with traditional imaging and surgical removal and will be the subject of Dr Rodney’s PhD thesis.
Professor John Kelly, Dr Andrew Feber, Simon Rodney