Cancer Research UK PhD Studentships
Now recruiting for 2017-18 entry
Application Deadline: 25 May 2017
(Interviews to be held on 20 June 2017)
Our Institute has an international reputation for cancer research, with world renowned experts in the field.
As part of our comprehensive training programme, fully funded by Cancer Research UK, we have funding for 2 further PhD studentships to commence in September 2017.
Our training programme aims to develop a cohort of scientists equipped both intellectually and technically to conduct the highest quality research on cancer.
Our research degrees are supplemented by a comprehensive support programme, providing training in a wide range of biomedical laboratory methods and other vital transferable skills.
We are now inviting applications for the following projects:
Disrupting the stemness signalling network in pancreatic cancer to prevent disease relapse
First Supervisor: Professor Christopher Heeschen
Second Supervisors: Dr Gabriella Ficz
Pancreatic cancer is a highly metastatic cancer with still very low 5-year survival due to its aggressive nature and lack of effective therapies. We have now provided conclusive evidence down to a single cell that pancreatic cancer stem cells (CSC) are driving tumour growth and metastasis. We have performed very substantial in vivo RNAi screens in pancreatic CSC and identified various novel targets including a super-enhancer element controlling the stemness signalling network in pancreatic CSC. Our preliminary data already strongly support our hypothesis that its inhibition, which can be achieved with available compounds, results in the collapse of the stemness network in CSC and subsequently induces their differentiation. This results in chemo-sensitisation and enhanced treatment response. For this PhD project the specific aims are:
Aim 1 – Provide comprehensive in vivo data using novel murine and human pancreatic cancer models to demonstrate its preclinical value for targeting CSC
• Switchable genetic targeting in normal and pancreatic cancer mice.
• Pharmacological inhibition in human and mouse models of pancreatic cancer.
• Combination treatment with advanced chemotherapy in order to target all pancreatic cancer cells.
Aim 2 – Define the molecular mechanism of action
• Functionally validate a specific pluripotency-associated gene as the most relevant downstream targets in CSC.
• Identify other putative binding partners and direct targets using mass spectrometry and ATAC-Seq/GRO-Seq.
To aid in the further dissection of the mechanism of action, we have established advanced multicellular 3D in vitro models using circulating CSC from patients with advanced disease. In vivo models of metastatic pancreatic cancer and a newly engineered switchable mouse model are readily available for comprehensive preclinical studies. In vivo imaging of CSC content will be used for tracking treatment response.
Uncovering the molecular pathways controlling tumour: CAFs crosstalk in RAS-driven lung tumours
First Supervisor: Dr Esther Castellano-Sanchez
Second Supervisor: Dr Martin Knight
KRAS mutations occur in 30% of lung tumours, are associated with poor prognosis and an exclusion criterion for some treatments. A better understanding of the biology of RAS-driven lung cancer will help design more effective therapies.
Using a KRAS-driven lung cancer mouse model in which RAS binding to its effector PI3-Kinase (PI3K) can be disrupted we found that RAS-PI3K signalling is essential for lung tumour initiation and maintenance. We have strong evidence that blocking RAS-PI3K signalling modulates activity of proteins essential for the extracellular matrix remodelling by cancer associated fibroblasts (CAFs), indicating that RAS-PI3K is essential to shape the tumour microenvironment that sustains tumour growth.
The goal of this project is to determine how RAS-PI3K signalling in CAFs modulates their gene expression patterns and ability to remodel the ECM in order to support tumour growth. It also aims to investigate the molecular mechanisms by which RAS-PI3K signalling controls ECM stiffness. Finally, clinical data sets and CAFs obtained from patient samples will be used to validate the clinical significance of our findings.
This project represents a highly novel approach that aims to identify essential signalling networks and mediators of tumour-CAF crosstalk that could be targeted in combination with existing therapies for the treatment of lung cancer.
The role of the chemokine CXCL10 and its CXCR3 receptor in ovarian cancer
First Supervisor: Professor Fran Balkwill
Second Supervisor: Dr Esther Castellano-Sanchez
Chemokines and their receptors control movement of cells into and out of the tumour microenvironment. Recently we found that one particular chemokine, CXCL10, was present at high levels in ovarian cancer metastases and that its receptor CXCR3 was present on ovarian cancer cells. To understand the significance of these findings, this project will answer three questions: Is CXCR3 functional in ovarian cancer cells? What cells are producing CXCL10 and CXCR3 in ovarian cancer biopsies? Is CXCL10 modified post-translationally when it is made by cancer cells? The project will use a range of cell and molecular biology techniques, complex in vitro 3D human tumour microenvironment models, samples from patients with ovarian cancer and in silico modelling using existing RNAseq and protein databases from ovarian cancer tissues. Understanding the role of CXCL10 and its receptor in malignant cell growth and spread, as well as lymphocyte trafficking, could lead to novel approaches to immunotherapy. Directly inhibiting the actions of this chemokine receptor pair or the post translational modification of the chemokine, may complement existing therapies.
Characterisation of novel PD-L1-like Immuno-Regulators and their Role in Lung Cancer Biology
First Supervisor: Dr Tyson Sharp
Lung cancer is the most common malignancy and the leading cause of cancer death globally. Although considerable advances in diagnosis and treatment of lung cancer have been made, the five-year survival rate of lung cancer is still poor. Therefore, it is imperative to further investigate the underlying mechanism of lung tumourigenesis and identify new targets for diagnosis and novel treatments. We have recently found that a deregulation of miRNA-silencing and hypoxia in cancer can affect tumour immunity. This PhD project will characterise new PD-L1-like immunoregulators and potential checkpoint inhibitors as novel biomarkers and targets for the development of immunotherapeutics in a panel of in vitro and in vivo lung cancer models.
Specially, this project will explore next-generation sequencing (RNA-Seq) data from human primary cells where there is defective hypoxic and miRNA signalling, recapitulating two key deregulated processes in many cancers. We will examine which mRNA and proteins are differentially expressed and also, from our preliminary analysis, which of these candidates have similar expression profiles and gene regulatory characteristics similar to those of PD-L1 and CTL4A.
This project is very novel and promises to produce significant amounts of new data and biology with respect to the exciting field of immune-oncology. Furthermore, this project will build the student’s skills in analysing NGS data and RNASeq, molecular cell biology and in vivo models of tumourigenesis, giving the student a fully rounded training in molecular oncology.
Translational regulation by oncogenic KRAS signalling in pancreatic adenocarcinoma
First Supervisor: Dr Faraz Mardakheh
Second Supervisors: Professor Nick Lemoine
All cells in our body contain the same genes, yet these genes are expressed in vastly diverse manners, allowing distinct cells to acquire different functions. Importantly, gene expression is altered in diseases like cancer, resulting in acquirement of undesired characteristics such as unrestricted cell proliferation and invasiveness. Gene expression is a multi-step process, beginning with transcription of RNA from DNA, followed by RNA processing and maturation, and ending in translation of proteins, the ultimate functional products of most genes, from RNA molecules. Importantly, while the impact of many oncogenic signalling pathways on transcriptional regulation is relatively well-studied, little is known about how these pathways modulate gene expression at the level of translation. Moreover, how transcriptional and translational inputs are integrated in order to induce and maintain a malignant phenotype is not known. Focusing on mutant KRAS, a major human oncogene responsible for more than 90% of all pancreatic adenocarcinomas (PDACs), the aim of this project is to use a multi-omics approach to assess how oncogenic signalling regulates translation of cellular proteins in PDAC, and how this regulation is integrated with modulation of transcription in order to trigger and support malignant cellular phenotypes such as unrestricted proliferation and invasiveness.
In this project, the PhD candidate will work with a switchable mutant KRAS model of PDAC, and learn to use next-generation sequencing, quantitative proteomics, and a variety of bioinformatics tools for analysis and integration of proteomics and transcriptomics data. They will also learn to use various cell based and biochemical assays, to evaluate the functional impacts of translational regulation on mutant KRAS induced malignancy.
Using vascular promotion to improve the efficacy of immunotherapy
First Supervisor: Professor Kairbaan Hodivala-Dilke
Second Supervisor: Professor John Gribben
Immunotherapy has probably provided the best opportunity to improve the out come of cancers that otherwise lack effective treatment. One limitation of immunotherapy is ensuring a high level of access to the cancer microenvironment. Thus increasing immunotherapy delivery to tumours, whilst enhancing drug uptake and reducing side effects, is a primary goal of modern cancer research.
In mouse and human cancer models of both lung cancer and pancreatic ductal adenocarcinoma in vivo, we have shown that co-administration of low dose Cilengitide and Verapamil increases tumour angiogenesis, and blood flow specifically in tumours, a strategy we have termed vascular promotion. (Wong et al., Cancer Cell 2015).
The proposed PhD will combine the use of in vivo cancer biology with cell and molecular biology to examine the utility of vascular promotion in combination with immunotherapy as novel strategy to improved cancer therapy.
Overcoming resistance to arginine deprivation therapy in mesothelioma
First Supervisor: Dr Sarah Martin
Second Supervisor: Dr Peter Szlosarek
The prognosis for patients with the asbestos-related disease, malignant pleural mesothelioma, remains poor. We have previously identified an Achilles’ heel whereby depriving the amino acid arginine selectively kills mesothelioma cells. This metabolic quirk of mesothelioma cells is due to loss of the enzyme ASS1, which makes arginine in otherwise healthy cells in our body. This has recently being tested in a multicentre clinical trial in patients across the UK. About 50% of mesotheliomas do not express the ASS1 gene and therefore depend on a steady supply of arginine from the bloodstream for their growth and can be killed if arginine is suddenly removed. Although arginine starvation can be achieved with arginine blockers such as ADI-PEG20, recent data has shown that these tumours can become resistant to this therapy. We have generated a cell model in the lab that mimics resistance to this therapy, in order to investigate what underlies the resistance and also to identify new ways of treating these tumours. We have identified drugs, called polyamine inhibitors that may be able to exploit the loss of ASS1 and alleviate the generation of resistance. In this PhD project, we will investigate this targeted therapy in laboratory cell models and in patient samples from clinical trials. Identified therapies that overcome this resistance will be taken forward into the clinic.
Dissecting the role of exosomes on microenvironment remodelling in PDAC
First Supervisor: Dr Susana Godinho
Second Supervisor: Professor John Marshall
Pancreatic Ductal Carcinoma (PDAC) is characterised by poor prognosis due to late diagnosis, high metastatic potential and resistance to conventional therapies. The tumour microenvironment is thought to contribute to the PDAC aggressiveness and resistance to therapy, and this is partly due to the activation of pancreatic stellate cells (PSCs). Thus, understanding how PSCs are activated is crucial for the development of more effective therapies to treat PDAC patients. We recently discovered that cancer cells containing extra centrosomes, a common feature of human tumours, secrete higher amounts of extracellular vesicles (exosomes), which activate PSCs. In this project, we will assess how exosomes activate PSCs and how this contributes to PDAC invasion:
Aim1. Profiling of exosomes secreted by cells with extra centrosomes. Isolated exosomes will be analysed by mass spectrometry to identify the proteins that are contained in these vesicles.
Aim2. Identify the exosome components that play a role in PSCs activation. siRNA screen will be used to determine the exosomal proteins important to activate PSCs.
Aim3. Role of secreted exosomes in PDAC invasion. Using 3-D organotypic models, we will test if activation of PSCs with isolated exosomes promote PDAC invasion and which of the identified proteins are required for this process.
Frequently Asked Questions
How do I apply?
You should email your application to firstname.lastname@example.org. Your application will need to include:
- Application Form
- 2 References - BCI Reference Request Form
- Resume/Curriculum Vitae (CV)
- Personal Statement
- Academic transcripts
- Proof of English Language Proficiency (if applicable)
Incomplete applications will not be considered.
Can overseas students apply?
Yes, students from all countries are invited to apply for the studentship, however the studentship will only cover the Home/EU equivalent proportion of the fees.
If, for fee purposes, you are classified as an overseas applicant, you will be responsible for paying the difference between the Home/EU and overseas rate.
What is the stipend?
In addition to the Home/EU tuition fees paid on a student's behalf, the CRUK studentship provides a tax free annual stipend of £21,000.
How many projects can I select?
You can select up to 2 projects on your application.
I previously applied for one of the projects listed. Can I apply again?
We have received funding for an additional 2 studentships which is why we have readvertised some projects. If you have previously applied for one of these and wish to be reconsidered please e-mail email@example.com to notify us of this.
What is the duration of the studentship?
You will be expected to complete and graduate within 4 years.
Your stipend payment will be for 3 years.
What degree will I receive?
You will be registered at and awarded your PhD degree by Queen Mary University of London.
Are there any English language requirements?
If English is not your first language, or you do not have an undergraduate degree taught in a Majority English speaking country, you will need to show evidence of English proficiency.
What are the academic requirements?
You need to have, or expect to gain, a first or upper second-class honours degree or equivalent, in a relevant subject.
When will I hear whether I will be invited to interview?
Shortlisted candidates will receive an emailed invitation to interview the week commencing 12 June. If you do not hear from us by the end of this week, please assume your application has been unsuccessful on this occasion.
What is the interview process?
The interviews will take place at Barts Cancer Institute, Charterhouse Square, London.
Interview date: 20 June 2017.
If shortlisted, you will be interviewed by a panel, who are independent of the project supervisory teams.
As part of the shortlisting process you may be contacted by a member of the project supervisory team for an informal interview with the opportunity to visit the labs.
How will you contact me?
Throughout the application and interview process, we will contact you using the email address that you provide on your application form; so please check it regularly. We may also contact you by telephone.
Who should I contact if I have a question?
If you have a question about a specific project please contact the supervisor directly. For general enquiries about the PhD studentship or application process please contact firstname.lastname@example.org
If I am successful, when will I start my PhD?
You will enrol for your PhD on 26 September 2017.