Former Fellows
Shivani Bailey
Supervisors: Dr Matthew Murray and Professor Nick Coleman
Targeting oncogenic microRNA clusters in malignant germ cell tumours using tiny locked nucleic acids
Germ cell tumours (GCTs) affect babies, children and young people. They occur in the gonads (ovaries/testes), but also in other sites, including the brain. At present, treatment regimes include a combination of surgery, chemotherapy and/or radiotherapy. Although most patients with malignant GCTs do well, some patients still have poor outcomes. For those that survive, many suffer long-term effects of treatment, including permanent damage to hearing, the kidneys, lungs and heart.
MicroRNAs are short, non-coding RNAs that regulate the expression of genes in cells, so abnormal microRNA levels may lead to cancer. Dr Matthew Murray and the Coleman group have identified two ‘clusters’ of microRNAs that are at very high levels in all malignant GCTs. These particular microRNAs are present at very low or undetectable levels in healthy human cells. We aim to block the effects of these microRNAs using specific inhibitors called tiny LNAs.
We ultimately aim to develop a novel therapy to improve clinical outcomes for patients with malignant GCTs by improving survival of patients with high-risk tumours and reducing toxic effects of hemotherapy for patients with low-risk disease.
Suzanne Murphy
Supervisors: Dr Nitzan Rosenfeld – Cancer Research UK Cambridge Institute, Dr Pippa Corrie& Mr Amer Durrani – Cambridge University Hospitals
Melanoma, the most aggressive form of skin cancer, results in 2,203 deaths per year in the United Kingdom and its incidence has increased faster than any other cancer. Melanoma invades and metastasizes early and is resistant to conventional chemotherapy. There are no reliable biomarkers of disease response to treatment. The development of targeted therapies, including BRAF and MEK inhibitors, has provided increasing evidence that genetic events are responsible for response and resistance to therapy. With this in mind, the MelResist study is exploring the genetic basis of resistance to these therapies.
Circulating tumour DNA (ctDNA) is emerging as a non-invasive method to monitor tumour changes. The Rosenfeld lab at the Cancer Research UK Cambridge Institute (CRUK CI) have demonstrated the potential of cell free circulating tumour DNA (ctDNA) as a non-invasive liquid biopsy for personalized cancer therapy in a number of advanced cancers, including breast, ovarian and lung cancer. The group have developed a low-cost, high-throughput method called tagged-amplicon deep sequencing (TAm-Seq) which allows identification of cancer mutations in plasma at allele frequencies as low as 2%, with sensitivity and specificity of >97%.[1] (Forshew et al. Sci Transl Med 2012).
Developing a technique of detecting ctDNA in the plasma and/or urine of melanoma patients has the potential to revolutionize the management of this life-threatening disease. To be able to measure tumour burden and specific mutations during the course of treatment could guide clinicians regarding whom to continue targeted therapy and equally predict patients likely to relapse. Detection of mutations responsible for resistance to targeted therapies will aid the development of second line therapies. In addition, detection of ctDNA may be of prognostic value in melanoma patients undergoing resection of their primary or locoregional disease who are at high risk of recurrence, so that targeted therapies could be utilised at an earlier stage of their treatment.
Keval Patel
Supervisor: Dr Nitzan Rosenfeld – Cancer Research Uk Cambridge Institute
Prostate cancer is the most common male cancer in the UK affecting 50% of 50-year-old men. Many men have indolent disease that would not limit their life span. Some however, have aggressive disease that will progress if not treated. Current monitoring methods e.g. blood tests or prostatic biopsies, are unable to distinguish accurately between indolent and aggressive disease. This is partly because, in the prostate gland of a single man there can be multiple cancer foci.
Patients with cancer have mutations in their DNA and, recent studies show that these mutations can be tracked non-invasively through simple blood tests (circulating tumour DNA or ctDNA). This project will investigate the ability of ctDNA to display and monitor the complexity of prostate cancer in men.
We hope that in the future, ctDNA analysis could be used to non-invasively predict aggressive cancers and stratify men to early aggressive treatment to improve outcomes.
Alex Riding
Supervisor: Dr Menna Clatworthy – Department of Medicine, MRC Laboratory of Molecular Biology
Identifying and characterising the role of renal innate lymphoid cells
Acute kidney injury is an important pathology complicating multiple diseases and affecting nearly a fifth of all inpatients. While there are many potential causes, the process is mediated by a renal inflammatory state causing cell death and ultimately kidney failure. Certain immune cells play a critical role in initiating and potentiating this inflammation by producing pro-inflammatory molecules, notably IL-17 and IL-22. Th17 cells are the primary source of these molecules, however increasing evidence is mounting that a new class of immune cells, innate lymphoid cells, may also play a role.
Innate lymphoid cells have been extensively characterised in the gut, lung, skin and blood. My work will seek to identify these cells within the human kidney and elucidate their role in renal inflammation.
Dan Greaves
A forward genetic screen to identify genes required for silencing HIV
The remarkable success of Highly Active Anti-Retroviral Treatment (HAART) has transformed the life expectancy of patients with HIV. Whereas infection with this virus was previously fatal, the disease can now be controlled but requires lifelong treatment with HAART. The remaining challenge is the reservoir of latent provirus which integrates into the genome of non-dividing T-cells and is insensitive to anti-viral treatment. The maintenance of this latent virus pool is complex and only partially understood.
The aims of my project are to identify and characterise novel host cell transcriptional repressors which are involved in silencing HIV. To do this I will use a forward genetic screen in haploid cells to identify HIV silencing complexes and then perform a biochemical analysis to determine how these complexes work. A detailed understanding of the cellular processes involved in the initiation of HIV latency has the potential to lead to improved treatments against the virus, as elimination of the latent reservoir of HIV could theoretically cure this devastating disease.