Christie OncoBEAM RAS (COBRA) Study
Dr Mark Saunders, The Christie NHS Foundation Trust
The intended research is the Christie OncoBEAM RAS (COBRA) study to evaluate the performance of OncoBEAM RAS testing on plasma cell-free ctDNA to Standard of Care RAS testing on formalin fixed, paraffin embedded tumour tissue in patients with metastatic colorectal cancer. This study is critical to evaluate whether the OncoBEAM RAS test may be adopted for use for routine patient care in the UK.
The study is a collaborative research project involving oncology and accredited clinical laboratory services in Cardiff and in Manchester, with funding and OncoBEAM RAS testing supported by Sysmex Inostics.
ctDNA in Colorectal Cancer
Dr Richard Adams, Cardiff University
Over the past decade, the advancement of sequencing technologies has greatly improved our understanding of the mutational spectrum of colorectal cancer (CRC). We now have greater knowledge of the location of ‘hotspots’ where mutations are likely to occur, which can affect treatment and prognostis. We can apply this knowledge by interrogating circulating biomarkers such as circulating tumour DNA (ctDNA), exosomal nucleic acids and tumour educated platelets (TEPs) and proteins in patient blood. Exosomes are cell-derived vesicles that are present in many biological fluids. TEPs are platelets, which have been shown to sequester cell-free nucleic acids.
ctDNA levels within plasma have been investigated as a sensitive method of monitoring patients and predict relapse and response to treatment in certain cancer types. Circulating exosomes originate from tumour and/or wild type cells, providing nucleic acids with more structural stability and preventing degradation. We plan to use exosome, platelet and protein isolation techniques with sequencing to interrogate and compare all biomarkers in CRCs at diagnosis and throughout therapy.
These studies may provide clinicians with a non-invasive method with which to assess patient response and monitor progress. This has potential implications in choice of treatment and enables clinicians to halt toxic treatments that appear ineffective.
Development of Personalised treatment in Ovarian and Colorectal Cancer
Dr Karen Keating, Almac Diagnostics
Almac have discovered and validated two molecular signatures to support personalised treatment in breast and ovarian cancer, namely the DNA Damage Repair Deficiency (DDRD) and Almac Angiogenesis (AADx) assays, respectively. The DDRD Assay identifies breast cancer patients that are likely to benefit from DNA damaging chemotherapies and the AADx assay identifies a subgroup of high grade serous ovarian cancer (HGSOC) patients that have superior survival on standard of care chemotherapy. The aims of this study are to expand the utility of the AADx assay into the neo-adjuvant treatment setting of ovarian cancer and to evaluate both signatures in the metastatic colorectal cancer (mCRC)setting.
Investigating Exosomes and their Influence on Prostate Cancer Development
Dr Jason Webber, Cardiff University
For several years we have explored how cancer cells hijack the function of non-cancerous cells leading to enhanced tumour growth and aggressive disease. Our research has focused on tiny bubbles of fat, termed exosomes. Exosomes are extremely complex and consist of various components including proteins plus genetic material (such as mRNA). These components act as messages that can be conveyed from one cell to another, both within the surrounding environment and to distant sites within the body.
Many of the components contained within exosomes are specific to the cell from which the exosome was released. We have identified several proteins and mRNAs, contained within prostate cancer exosomes, which are key drivers of disease-associated changes within the tumour microenvironment leading to enhanced tumour growth and metastasis. It has, however, been demonstrated that cancer exosomes can be isolated from patient blood and may therefore serve as indicators of disease. Using previously established methods, developed using Prostate Cancer UK Career Development Fellowship; serum and urine samples from WCB (Dr A Clayton), we will isolate exosomes from patient serum and identify novel exosomal-markers capable of discriminating patients with aggressive prostate cancer from those with slow growing indolent tumours.
Development of Automated Technology for use in Clinical Pathology
Dr P Hamilton, Philips Digital
The reason behind our need for lung slides is an ongoing research program into the automatic identification of tumor on histological slides (Initially Lung NSCLC). Slides will be scanned at 40x on the Philips slide scanner. The resultant image will form the basis for the application of image analysis techniques to identify tumor via a boundary. This would be achieved by training a classifier to distinguish between tumor and non-tumor. This mark-up can be used to suggest a region of the case which is suitable for macro-dissection purposes. We would propose to acquire a large cohort of lung cases (initially) for training and validation.
This algorithm we propose can be rolled out across many tissue types and we currently have a need for lung, colorectal, breast, prostate and ovarian tissues (we are currently focusing on lung initially). We would be hoping to get somewhere between 1000 – 3000 slides per tissue type (not all from a single source) which would will require 100+ slides from each organization. Suffice to say we are looking for large amounts of cases.
Validation of a Novel Compound for the Treatment of Prostate cancer
Dr R Clarkson, Cardiff University
We have developed a novel experimental anti-cancer agent that evidence suggests would be particularly effective at treating prostate cancer patients who have a high risk of their tumour spreading to other parts of their body. In order to confirm this we propose to test the novel agent (OH14) on tumours taken directly from prostate cancer sufferers, to determine if this agent works in the near clinical setting. If it does, we will establish which tumour types are most sensitive to the treatment, and whether this agent also improves the efficacy of existing therapeutics that are currently used in the clinic. This study will involve the establishment of a new supply route of fresh prostate tumour tissue to be grown from prostate cancer patients and maintained in the laboratory in Cardiff. Optimising and establishing this pipeline of fresh prostate cancer material will be a valuable technique for the prostate cancer research community.
Exploring Drug Resistance in ER+ Breast Cancer
Prof W J Griffiths, Swansea University
In 2011, just under 50,000 women were diagnosed with breast cancer (BC) in the UK, of which about 70% are classified as estrogen receptor α positive (ER+). This means they produce high levels of a particular protein called the “estrogen receptor α” (ERα) in cancer tissue. People with ER+ BC respond well to existing drug treatments. Despite this, however, a complete cure for ER+ BC is hindered by the body becoming resistant to drug therapy over time and the cancer may reoccur after 5 years of drug treatment.
For ERα to have harmful effects in tissue and promote BC it needs to be “turned-on” by a small molecule. The sex hormone 17β-estradiol can activate ERα and the class of BC drugs called aromatase inhibitors stop the production of 17β-estradiol in postmenopausal women, this means that less 17β-estradiol is available to stimulate the growth of ER+ BC cells. New research from America suggests that other small molecules made by the body may also activate ERα and trigger BC even in people undergoing aromatase inhibitor treatment.
We hypothesise that these small molecules, called hydroxycholesterols, may explain the resistance to drug therapy in some people with ER+ BC. In this study we will test the hypothesis by analysing blood serum from people with BC and people without BC and determine the concentrations of hydroxycholesterols. Results from this study will improve our understanding of ER+ BC and give hints towards new drug treatments.
How Stress can effect response to Chemotherapy in Triple Negative Breast Cancer
Dr M Flint, Brighton University
Stress hormones have been shown to reduce the effectiveness of chemotherapy drugs commonly used to treat one of the more aggressive types of breast cancer - Triple Negative Breast Cancer. Some changes in DNA (the building blocks of cells) are thought to affect the bodies’ response to stress and so our goal is to determine whether one of the most common changes in DNA makes a patient less likely to respond well to treatment.
We intend to find out how common the DNA variation is in Triple Negative Breast Cancer patients by examining breast tumour tissue and comparing our findings to the treatments and outcome of the patients. We would like to be able to predict a patients’ response to chemotherapy and determine whether medications to reduce stress or therapies, such as meditation (which also reduce stress) may improve treatment outcome, experience and survival prospects.’