2013 Grants

Dr Ramsay McFarlane, Bangor University – Post-doctoral fellowship

Project Title: Application of systematic genome scale analyses of germ line genes: biomarker and oncogenic potential.

Amount: £99,815

Duration: 24 months

The development of new diagnostic and therapeutic strategies aimed at increasing cancer survival rates has been significantly impeded by the fact it is difficult to distinguish cancer cells from the normal, healthy cells from which they are derived. We have recently identified a group of human genes which are normally switched on only in a part of the body which is not recognised by the body’s immune system as self, the testes, but are aberrantly switched on in a range of cancers. These genes can provide a very powerful tool for diagnosing the presence of cancer early and for providing targets for a range of new potential therapies. We initially identified these genes by screening the vast amounts of cancer genetic data which are stored in publically available databases. This current proposal will enable us to take this work further and identify new biological markers for cancer, thus enabling us to expand our very limited arsenal of biomarkers to target this complex disease.

Dr Paul Shaw, Velindre Cancer Centre and Cardiff University – PhD studentship

Project Title: Developing stem cell containing organoids from primary and metastatic human colorectal cancer for preclinical studies of stratified colorectal cancer therapeutics.

Amount: £104,280

Duration: 36 months

We aim to set up and validate a new 3D tissue culture (organoid) system that will permit growth of primary or secondary (spreading) tumours from bowel cancer patients to enable the assessment of new drug therapies in a timely and therefore cost effective way. Such developments in tissue culture should revolutionise drug discovery in the laboratory by providing normal and cancerous cells that closely match their counterparts within patients. Mutations in patients’ tumours are important in terms of treatment responses and our expectation is that 3D tissue culture will be a more accurate model of assessing drug responses than current techniques (cancer cell lines grown in culture or in animals). In collaboration with the Wales Cancer Bank all collected patient tumour samples will undergo systematic gene mutation analysis to ensure that the characteristics of cancer cells grown as organoids carry sufficient similarity to those found in respective patients’ tumours. This data will be used to ensure that this new technology is fit for purpose and able to test targeted drug delivery in the presence of known tumour characteristics. This work may ultimately allow us to accurately predict novel drugs or drug combinations most likely to be effective according to the genetic and cellular features present in 3D tissue culture and by implication the original ‘parental’ tumour.

Dr Richard Darley, Cardiff University – PhD studentship

Project Title: Mechanisms dysregulating canonical Wnt signalling in acute myeloid leukaemia

Amount: £116,747

Duration: 36 months

Despite gradual improvements in treatment outcomes, most patients with acute myeloid leukaemia (AML) still die from their disease. Hope for further improvements in AML treatment now lie with targeted therapies. AML is a highly variable disease making it difficult to treat, however, a unifying feature of this disease is that normal

blood cell development is blocked. Wnt signalling is a key developmental regulator. The key to Wnt signalling is the entry of a protein, called β-catenin, into the nucleus of the cell where it effects changes in gene expression. Normal blood cells resist entry of β-catenin into the nucleus. In contrast, in AML high levels of β-catenin accumulate in the nucleus of a large proportion of patients and patients exhibiting this abnormality have a poorer treatment outcome. The key defect shown by AML blasts is the nuclear entry of β-catenin. Blocking the entry of β-catenin into the nucleus would be a key therapeutic axis. This project therefore seeks to identify the factors influencing nuclear localisation of β-catenin. We will examine this from two perspectives: the identification of partner proteins of β-catenin which mediate its accumulation in the nucleus and the identification of signalling molecules produced in the bone marrow of AML patients which might be influencing this process.

Dr Steve Hiscox, Cardiff University – PhD studentship

Project Title: Exploring the impact of anti-oestrogen resistance on the capacity of breast cancer cells to modulate bone cell function.

Amount: £85,281

Duration: 36 months

Acquired resistance to anti-oestrogens occurs in over a third of breast cancers leading to disease progression which frequently occurs as bone metastasis. Breast cancer cells that spread to the bone can alter the way in which bone cells function, changing them into cells that actively degrade bone tissue. This results in significant bone loss and biochemical alterations from within the bone tissue that in turn support breast cancer cell survival and growth. Using breast cancer cell models, we have shown that acquired resistance to anti-oestrogens results in the development of highly aggressive cell characteristics and the ability to modulate the behaviour of non-cancerous cell types in a way likely to promote metastasis. Our recent evidence now suggests that resistant breast cancer cells also overexpress a number of bone-regulatory growth factors and are able to induce bone cell precursor cells to change into osteoclasts, a type of mature bone cell which actively degrades bone tissue. These effects appear to be dependent upon the expression of Src kinases in breast cancer cells. The aim of this PhD project is thus to explore further how anti-oestrogen resistance alters the capacity of breast cancer cells to influence bone cell behaviour and elucidate the role of Src in this process with a view to its potential as therapeutic target through which bone metastasis might be suppressed.

Dr Andrew Godkin, Cardiff University – Post-doctoral fellowship

Project Title: Exploring the nature of anti-tumour T cell responses to design better treatment and screening of patients with colorectal cancer.

Amount: £163,721

Duration: 36 months

Our laboratory has been working on colorectal cancer (CRC), one of the most common malignancies, since arriving in Cardiff in 2003. We have strong evidence that the anti-tumour immune response, which can confer benefit by controlling/destroying cancer cells, is prevented from working effectively by a regulatory branch of the immune system. The overall aim of this project is to further our understanding of how the immune system attacks tumours and what prevents this from happening, in order to design better treatment and screening of CRC patients. Specific goals: (i) Cancer Research Wales has strongly supported a vaccine trial that we are running in CRC patients. We wish to maximise the data obtained by an in-depth analysis of >800 frozen patient samples to understand in detail how immune responses are generated and controlled in subjects. (ii) Preliminary results suggest that the presence of CRC can be indicated in blood tests through measurement of the anti-cancer immune response. This offers the exciting prospect of designing a simple blood test to screen for CRC. (iii) We have identified a novel population of regulatory cells that survive within the cancer, inhibiting useful local immune responses. We will investigate selective blockade of this population, to unleash potent cancer-killing immune responses.

Professor Duncan Baird, Cardiff University – PhD Studentship (Partnership Grant)

Project Title: Investigating 8p22 Fusion Breakpoint Hotspot Activity

Amount: £55,239 (50% of total costs)

Duration: 36 months

A telomere is a specific repeated DNA sequence that caps the end of each chromosome in order to prevent deterioration of the chromosome or to prevent chromosomal binding to other genomic regions. We have been examining the mechanisms underlying telomere fusion and how this process can drive genomic instability creating the types of lesions commonly found in human tumours.  One aspect of this work is to understand the extent to which telomeres undergo fusion with non-telomere genomic regions and to identify if specific regions of the genome are prone to fusion with telomeres. We have established a large robust dataset that has allowed us to identify several regions of the genome that have a clear propensity to undergo fusion with dysfunctional telomeres.  Two of these loci on chromosomes 8 and 11 display intense fusion hotspot activity, and both are associated with chromosome arms that are frequently lost in many tumour types. This project will focus on characterising the hotspot on 8p22, this region is close to fragile sites FRA8A&B and is subjected to rearrangements in several tumour types including breast and prostate. With the exception of the rare fragile sites often characterised by triplet repeat expansion, fragile sites have been poorly defined at the molecular level; we anticipate that our data may help towards a definition of the molecular determinants of common fragile sites.

Dr Alan Parker, Cardiff University – Technician (Partnership Grant)

Project Title: Evaluating novel oncolytic adenovirus/chemotherapy combinations for effective, stratified cancer therapeutics

Amount: £75,870 (50% of total costs)

Duration: 36 months

Drug resistance represents a major problem for conventional cancer treatments. To overcome this, many researchers are focussing on developing “tamed” forms of viruses to treat cancer by genetically mutating them so that can they replicate and kill only cancer cells.  This is commonly known as “virotherapy”, and the viruses utilised, “oncolytics”.  Amongst the oncolytic viruses best studied are a class of viruses known as adenoviruses that causes mild infections of the respiratory tract.  Of the 57 different types of adenoviruses that have been discovered to date, only one, Ad5, has been studied in detail for its ability to treat cancer.  Whilst Ad5 shows potential, its use as an oncolytic is limited by the significant proportion of individuals who have been exposed to the virus previously (ranging from 40-95% of the population, depending on ethnicity), and whose immune system recognises and clears the virus following administration. Furthermore, the Ad5 receptor, CAR, is not expressed on the majority of tumours. This proposal will therefore seek to develop new types of adenoviruses and evaluate their potential as oncolytics for cancer treatment, and to establish maximal efficacy as a cancer treatment in combination with conventional chemotherapy drugs and/or anti-angiogenics.

Dr Andrea Brancale, Cardiff University – PhD studentship

Project Title: Discovery of Bcl-3 inhibitors for the potential treatment of metastatic breast cancer

Amount: £104,280

Duration: 36 months

Although treatment options have improved recently for some types of breast cancer (e.g. ductal carcinoma in situ), the prognosis for invasive/metastatic forms of the disease remains poor. One particularly problematic form of breast cancer (15-25% of UK cases) is known as HER2 (ErbB2) positive disease, and is associated with invasive and metastatic disease. Recent developments in HER2 positive breast cancer therapy, including Herceptin, have had limited impact in this disease and are frequently associated with resistant disease. Pilot studies (Clarkson, co-applicant) have established a protein known as Bcl-3 as an exciting new HER2-positive breast cancer target. Bcl-3 leads to metastasis of HER2- positive mammary tumours without compromising normal mammary function. In addition, in vivo deletion of the Bcl-3 gene resulted in a dramatic reduction in metastatic lung tumours with no significant effect on primary mammary tumour growth. We have used computer modelling of the Bcl-3 protein to identify potential candidate molecules for subsequent chemical synthesis and anticancer evaluation. This project builds on and extends these pilot studies to bring together expertise in Bcl-3 biology, computational drug design and medicinal chemistry to develop novel and selective Bcl-3 inhibitor drug candidates with the potential to improve the treatment of invasive breast cancer.