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WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

PhD Studentships 2019 - Open Now

Application deadline - 3 December 2018, 1700 hrs GMT.

Available Projects

 

Esther Baena - Prostate Oncobiology

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Role of prostate stem cells and their niche in therapy resistance

This 4 year PhD studentship offered in Dr Esther Baena’s group based at the Manchester Cancer Research Centre (MCRC), South Manchester

Worldwide, Prostate Cancer (PCa) is the second most common cancer in men and the fifth leading cause of cancer related deaths worldwide. Clinically (PCa) is a very heterogeneous disease, but the underlying biology is only poorly understood. Although almost all patients respond to androgen deprivation, progression to metastatic castration resistant (CRPC) state is inevitable and fatal. To understand the molecular mechanisms of castration resistance is therefore important to improve treatment options for these patients.

Previous work from our group has identified a subset of PCa cells, which are inherently resistant to androgen deprivation and characterized by self-renewal capacity. Targeting of these cells may therefore constitute a new option to treat patients with prostate cancer. This PhD project will further characterize these cells and the cellular heterogeneity of prostate cancer, using single-cell transcriptomics and lineage-tracing experiments. The PhD candidate will benefit from our close collaborations with the Christie hospital, allowing to perform many of these studies on primary material from patients. In addition, our group employs mouse models of prostate cancer to translate findings from human tissues into an in-vivo scenario. This PhD project will also focus on the constitution of the prostate cancer niche, as it contributes to tumour evolution and growth. Single-cell technologies will be used to characterize niche cells in genetically defined PCa.

Funding

This position is funded by Cancer Research UK for the 4 year duration. The successful candidate will join the CRUK Manchester Institute & will be affiliated to the University of Manchester on the same studentship terms and conditions as all CRUK MI students.

The successful applicant will be awarded a non-taxable & national insurance free annual stipend of £19,000/annum plus payment of university tuition and bench fees.

Michela Garofalo - Transcriptional Networks in Lung Cancer

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Elucidating the role of the tumour microenvironment in non-small cell lung cancer

This 4 year PhD studentship offered in Dr Michela Garofalo’s group based at the Manchester Cancer Research Centre (MCRC), South Manchester

The tumour microenvironment plays a crucial role in tumour progression, clinical prognosis and treatment responses of cancer. Thus, a deeper understanding of the dynamic relationship between the expanding tumour and the surrounding tissue is a key factor for the development of new successful therapeutic strategies.

Cancer-associated fibroblasts (CAFs) are a major cellular constituent of the tumour stroma, and their interaction with cancer cells is implicated in various aspects of tumour biology. For example, CAFs can promote growth, invasion and metastasis of cancer cells. However, our knowledge of the molecular mechanisms involved in the cell-cell communication between cancer cells and CAFs is still limited. Accumulating evidence shows that tumour cells communicate with stromal cells in the microenvironment via secretion of microvesicles containing miRNAs. MiRNAs are small noncoding RNA molecules that regulate gene expression at post-transcriptional level and their exchange between cancer cells and CAFs can alter the expression profiles of CAFs to favour the progression of cancer.

By using 2D and 3D in vitro culture systems as well as pre-clinical models of lung cancer, we aim to elucidate the mechanisms of the interactions between cancer cells and CAFs and further explore the biological implication of the transfer of miRNAs between cancer cells and the surrounding stroma, with the final goal to identify new therapeutic targets in lung cancer.

Funding

This position is funded by Cancer Research UK for the 4 year duration. The successful candidate will join the CRUK Manchester Institute & will be affiliated to the University of Manchester on the same studentship terms and conditions as all CRUK MI students.

The successful applicant will be awarded a non-taxable & national insurance free annual stipend of £19,000/annum plus payment of university tuition and bench fees.

Claus Jorgensen - Systems Oncology

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Targeting the tumour stroma in pancreatic cancer

This 4 year PhD studentship offered in Dr Claus Jorgensen’s group is based at Alderley Park, Cheshire

Pancreatic Ductal Adenocarcinoma (PDA) has a dismal prognosis with a medium survival below 6 month and an average 5-year survival below 5%. This is due to the aggressive nature of the cancer, a lack of effective therapy and late diagnosis. The most frequent occurring genetic mutations have been identified with activating mutations in the oncogene KRAS and inactivating mutations in the tumour suppressor INK4A in more than 90% of all tumours and loss of TP53 and SMAD4 function occurring in 85% and 55% of all cases respectively.

PDA is characterized by an extensive tumour stroma, which has been shown to support tumour growth, metastasis and resistance to therapy. The tumour stroma is primarily composed of fibroblasts and cells of the immune system. Emerging data suggests functional diversity across the cellular entities in the tumour stroma, however the impact of individual stromal populations on therapeutic response is still unclear. As such, defining ‘resistance conferring’ stromal cell populations and delineating the molecular mechanisms by which they confer therapeutic resistance is critical to developing improved therapeutic strategies.

The Systems Oncology lab has a long-standing interest in understanding tumour-stroma interactions and how these interactions regulate tumour cell function (see Tape et al Cell 2016, Locard-Paulet et al Sci Signal 2016, Tape et al MCP 2014 and Worboys et al Nat Methods 2014). This project combines basic biological principles and translational research. The aim is to characterize the stromal impact on tumour-cell signalling and function through a combination of in vitro and in vivo techniques. This includes characterisation of therapeutic response using in vivo animal models of PDA and 3 dimensional ex vivo models by proteomics, single cell analysis (CyTOF, scRNAseq) and computational data integration.

Funding

This position is funded by Cancer Research UK for the 4 year duration. The successful candidate will join the CRUK Manchester Institute & will be affiliated to the University of Manchester on the same studentship terms and conditions as all CRUK MI students.

The successful applicant will be awarded a non-taxable & national insurance free annual stipend of £19,000/annum plus payment of university tuition and bench fees.

Angeliki Malliri - Cell Signalling

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Role of ubiquitin ligases in Non Small Cell Lung Cancer

This 4 year PhD studentship offered in Professor Angeliki Malliri’s group is based at Alderley Park, Cheshire

Lung cancer is the most commonly diagnosed cancer as well as the most common cause of cancer related deaths worldwide, with non-small cell lung cancer (NSCLC) being the major histological subtype. Despite growing knowledge of the molecular mechanisms driving lung cancer formation and progression, and the development of novel therapeutic agents, the overall 5-year survival of patients diagnosed with lung cancer remains less than 15%, indicating an ongoing need for innovation.

E3 ubiquitin ligases are a large family of proteins that catalyse the ubiquitination of many protein substrates, targeting them for degradation by the proteasome. Thereby, E3 ubiquitin ligases regulate a variety of cell processes including proliferation, apoptosis, migration and invasion. E3 ubiquitin ligases are often found overexpressed in human cancers, including lung cancer, and their deregulation has been shown to contribute to cancer development. Moreover, recent successes in the development of potent and specific small molecule inhibitors of E3 ligases have provided proof-of-concept that this is a druggable class of protein.

Previously, the Cell Signalling group lead by Professor A. Malliri at the CRUK Manchester Institute demonstrated the involvement of an E3 ligase in the regulation of lung cancer cell adhesion and motility (Cell Reports 10(1): 88-102, 2015). Recently, the group has identified an E3 ligase which appears essential for NSCLC formation in a widely utilised in vivo model. The successful PhD student candidate will continue this line of investigation by identifying substrates of the E3 ligase using proteomics and establishing the cellular processes regulated by ligase and substrate(s) and the underlying biochemical mechanism(s). Further, the student will address the role of the E3 ligase and substrate(s) in tumour maintenance in in vivo models, thereby validating these molecules as potential therapeutic targets. This will be further underscored by examining their expression and mutational status within human NSCLC tumour specimens, using histology and mining existing databases. The student will therefore be trained in a range of current molecular, biochemical and cell biological techniques, working with in vitro and in vivo models, and also database analysis in a vibrant laboratory environment with an extensive and documented track record in graduate student supervision.

Funding

This position is funded by Cancer Research UK for the 4 year duration. The successful candidate will join the CRUK Manchester Institute & will be affiliated to the University of Manchester on the same studentship terms and conditions as all CRUK MI students.

The successful applicant will be awarded a non-taxable & national insurance free annual stipend of £19,000/annum plus payment of university tuition and bench fees.

Tim Somervaille - Leukaemia Biology

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Misexpression of transcription factors in myeloid leukaemia

This 4 year PhD studentship offered in Professor Tim Somervaille’s group is based at the Manchester Cancer Research Centre [MCRC], South Manchester

Acute myeloid leukaemia (AML) is a cancer of the blood and bone marrow defined by a block to the normal differentiation of myeloid cells resulting in accumulation of blasts and failure of normal blood cell formation. Despite the genetic heterogeneity the differentiation block is the cardinal feature of the disease and emerging evidence reveals that mutations cluster in particular categories of gene. Indeed, the great majority of patients with AML have one or more mutations targeting a transcription factor, chromatin modifier or regulator of DNA methylation and this emphasises the absolute centrality of epigenetic and transcription factor dysfunction to the disease. Investigation of this dysfunction holds rich promise for discovery of new therapeutic targets for development through to the clinic: AML remains a significant cause of morbidity and mortality, with poor long-term survival despite treatments including chemotherapy and bone marrow (BM) transplantation.

An essential point is that we do not fully understand how the recurring genetic mutations in the disease confer the differentiation block. In recent years the Somervaille lab has uncovered new and unexpected transcription factor genes which make a frequent and substantial contribution. FOXC1 and IRX3, which are normally strongly repressed in haematopoiesis, are expressed at high level to functional effect in ~30% and ~40% respectively of the multiple genetic subtypes of AML associated with high HOXA/B gene expression (e.g. NPM1 mutated, MLL-translocated and t(6;9) cases).

Given these and other observations that transcription and epigenetic factor dysfunction is of central importance in AML, understanding how epigenetic dysfunction arises and contributes to the differentiation block holds rich promise for the identification of new therapeutic targets for patient benefit. In addition to killing leukaemia cells with chemotherapy, induction of differentiation is a major goal of treatment.

Through analysis of the AML chromatin landscape this project will make use of leading edge technologies and experimental approaches to discover how transcription factor genes FOXC1 and IRX3 are derepressed in AML to confer a differentiation block.

Key recent manuscripts that serve as a platform for the proposed project include:

  • TDD Somerville et al. Frequent derepression of the mesenchymal transcription factor gene FOXC1 in acute myeloid leukaemia. Cancer Cell 14:329-342.
  • TDD Somerville et al. Derepression of the Iroquois homeodomain transcription factor IRX3 confers differentiation block in acute leukemia. Cell Reports 22:638-652.

Funding

This position is funded by Cancer Research UK for the 4 year duration. The successful candidate will join the CRUK Manchester Institute & will be affiliated to the University of Manchester on the same studentship terms and conditions as all CRUK MI students.

The successful applicant will be awarded a non-taxable & national insurance free annual stipend of £19,000/annum plus payment of university tuition and bench fees.

Caroline Springer - Drug Discovery

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Proteolysis targeting chimeras (PROTACs): new approaches and applications to cancer

This 4 year PhD studentship offered in Professor Caroline Springer’s group is based at Alderley Park, Cheshire

The aim of the Drug Discovery Unit (DDU) is to discover new cancer drugs that utilise the fundamental discoveries made within the CRUK Manchester Institute (CRUK MI), the Manchester Cancer Research Centre, The University of Manchester and the wider research community. The DDU integrates medicinal, computational and synthetic chemistry with in vitro and cellular biology to provide new chemical entities for the treatment of unmet clinical need. Under the Directorship of Professor Caroline Springer, the Unit is actively progressing a portfolio of drug discovery projects against a variety of target classes in oncology disease indications.

PROTAC has emerged as a novel drug discovery strategy to achieve directed degradation of specific proteins within cells. Post-translational modification of proteins with ubiquitin chains is catalysed by ubiquitin ligases and is a key step in directing the respective proteins to proteasomal degradation. This approach creates alternative options to tackle traditionally “difficult to drug” proteins that are mutated or overexpressed in many cancers, and furthermore it leads to the removal of the target as opposed to inhibiting its catalytic function, potentially extending greatly the range of therapeutically tractable targets.

PROTACs are heterobifunctional molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. Dual binding of both components bring them in close proximity and initiate the ubiquitination followed by degradation. Several protein classes have been targeted successfully with PROTACs including transcription factors, kinases and epigenetic readers. The most commonly targeted ligases with PROTAC ligands are Cereblon and VHL. The nature and length of the linker between the two groups has a great impact on the efficacy of PROTACs.

There are several challenges to address in generating a successful PROTAC and its efficacy depends on the nature of the protein/ligase ligand pair, linkage site, linker length, and linker composition. An additional challenge is to generate compounds with cellular permeability and activity and eventually in vivo exposure and efficacy.

The aim of this studentship is to design and synthesise PROTAC molecules against targets with therapeutic potential in cancer, with initial focus on epigenetic modifiers such as SMARCA2, which is a key components of the SWI/SNF complex and is involved in chromatin re-modelling. The DDU has small molecule binders of one of the domains of the protein as well as suitable biological assays. The student will seek to optimise the PROTAC components, assisted by molecular modelling, and assess medicinal chemistry hypotheses for optimisation of the physicochemical and pharmacokinetic profile of these agents. A secondary aim of the studentship is to investigate and demonstrate proof of concept of less explored alternative PROTAC systems.

The successful candidate will learn synthetic and medicinal chemistry in the DDU and will become familiar with analytical chemistry, including the use of nuclear magnetic resonance, mass spectrometry and high performance liquid chromatography. The student will learn to use computational chemistry tools and knowledge of molecular modelling. He/she will gain an understanding of medicinal chemistry and drug design approaches and is expected to contribute and eventually take the lead on the design of new PROTACs. The student will also have the opportunity to learn biochemical and biological techniques such as enzymatic assays, cell culture and cell based assays.

Funding

This position is funded by Cancer Research UK for the 4 year duration. The successful candidate will join the CRUK Manchester Institute & will be affiliated to the University of Manchester on the same studentship terms and conditions as all CRUK MI students.

The successful applicant will be awarded a non-taxable & national insurance free annual stipend of £19,000/annum plus payment of university tuition and bench fees.

 

Postgraduate Study

A PhD should be an exciting and stimulating time. We are looking for talented and motivated graduates with backgrounds in biological sciences, mathematics, computer science and/or chemistry interested in pursuing scientific research careers.  As well as benefitting from dynamic and interactive research environment, graduate students will also have access to outstanding facilities within the Institute.  Our fully funded PhD studentships are of four years' duration with full sponsorship covering tuition, bench, and stipend fees for the duration of the study period.  Studentships are advertised annually (usually beginning of October) with interviews being held in January.   Students register with The University of Manchester to commence their PhD the following September.  Additional vacancies may be advertised throughout the year.  University registration entry points are also available annually in January or April.

On the 26 April 2017 The Paterson Building, which housed most of the Cancer Research UK Manchester Institute, suffered a major fire resulting in significant damage. We are striving to rebuild our world-class research facilities and we would like to make you aware that in the meantime, our studentships will either be at the Manchester Cancer Research Centre (MCRC) Building in South Manchester, which has excellent facilities to carry out research, or at the internationally-renowned life sciences campus at Alderley Park. After relocation we will return to our original site in Withington, Manchester, next to The Christie NHS Foundation Trust (Wilmslow Road, M20 4BX).

Eligibility

The EU Referendum and PhD Applications for 2019

The Cancer Research UK Manchester Institute is a proud to be a diverse, open, and global institution. Our priority, and that of the University of Manchester, is to support our current students and welcome new ones from Europe and other continents - we encourage students of all nationalities to apply for the programme.

We are pleased to announce that the UK Government's Department for Education has confirmed that students from the European Union, applying and commencing undergraduate and postgraduate university places in England in the 2019/20 academic year, will continue to be eligible for ‘home fee status’. This means they will be charged the same tuition fees as UK students for the duration of their studies, and even past the point that the UK leaves the European Union. For further information on funding support for EU students please visit https://www.gov.uk/government/news/further-financial-support-for-uk-and-eu-students.

Non-EU/international students do not have their tuition fees capped in this way. For further information on fee eligibility please visit https://www.ukcisa.org.uk/Information--Advice/Fees-and-Money/England-fee-status.

 

Applications are invited from recent graduates or final year undergraduates who have, or are expected to obtain a first or minimum of upper second-class honours degree or equivalent from any recognised university. Previous laboratory experience is not a requirement for acceptance to the PhD programme; however such experience will clearly give a realistic insight into academic research.

Applicants for our funded studentships are open to UK, EU and International students who should hold, or be about to obtain, a first or minimum upper-second undergraduate degree in a related subject area.  

English Language Skills (Non-UK Applicants)

Applicants from outside the UK will often need to meet specific English language requirements in order to be able to study at The University of Manchester. The UK’s Home Office requires that every student from outside the UK and the European Union (EU) must show evidence of a minimum level of English language (called B2 level) in order to be granted a UK visa ('Tier 4' visa) to study at undergraduate or postgraduate level. Minimum entry criteria means you must have gained a minimum overall score of 6.5 (and not <5.5 in each component and 6.0 in writing). For further information on English Language admission criteria please visit http://www.manchester.ac.uk/study/international/admissions/language-requirements/

It is not mandatory to provide documentation relating to your English Language skills during the application process. However, if you are offered a studentship, you will be required to provide such documentation in advance of University registration.

Postgraduates working at the CRUK Manchester Institute benefit from:

  • Access to world-class facilities, including deep sequencing, microarrays, mass-spectrometry, advanced imaging, histology, GCLP labs and flow cytometry
  • Core funding by Cancer Research UK, the largest independent cancer research charity in the world
  • A generous stipend of £19,000 per year (tax and NI free)
  • Tuition fees paid for the full four years
  • Group leaders focused only on research and postgraduate training
  • Working alongside over 350 postdoctoral scientists, clinical fellows, scientific officers, administrative and technical staff, postgraduate research students and visiting fellows
  • Being at the heart of the Manchester Cancer Research Centre, a partnership that brings together the expertise, vision and resources of its founding partners: The University of Manchester, The Christie NHS Foundation Trust and Cancer Research UK – all of which have formidable individual reputations in the fields of cancer treatment and basic and clinical research

For further information on the required documents to include with your application, see How to Apply.

Informal enquiries should be addressed to the Postgraduate Tutor at: pgt@cruk.manchester.ac.uk.

Self-Funding Students

If you have secured your own funding (stipend, tuition, bench and living fees) to undertake and support a PhD degree, and you are interested in study with a supervisor based at the CRUK Manchester Institute, you can submit an application directly to the University of Manchester for consideration; https://www.bmh.manchester.ac.uk/study/research/apply/   Your application should clearly state how you intend to fund your studies for the duration, and include supporting sponsorship and financial documentation.  You will need to select "PhD Cancer Sciences" as the programme description on the application form.  Please note, regardless of funding, the CRUK Manchester Institute PhD academic admission criteria remains as above: a first or upper second class honours degree and minimum level of English language qualification.

We are committed to training the next generation of cancer research scientists, helping launch careers in basic, translational and clinical cancer research. Postgraduate students enjoy a supportive environment, a challenging project and, together with tailored training in transferable and generic skills, development as independent scientists with excellent career prospects will ensue.