Eurizon.eu

Organization: Newcastle University

Location: Newcastle, UK

Field: Cancer Research

Requirements:

You should hold a first class or upper second class honours degree in a relevant subject. Further research experience and / or higher degree would be an advantage.

Abstract:

Chronic lymphocytic leukaemia (CLL) is very common and its variable disease course makes it clinically challenging. Although many patients respond to initial therapy, drug resistance is a major problem and the discovery of stratified medicines, translated into improved outcome is a high priority.

Description:

Chronic lymphocytic leukaemia (CLL) is very common and its variable disease course makes it clinically challenging. Although many patients respond to initial therapy, drug resistance is a major problem and the discovery of stratified medicines, translated into improved outcome is a high priority.
Genetic aberrations including del(17p)/TP53 mutation and del(11q)/ATM (ataxia telangiectasia mutated kinase) mutation hinder DNA damage response pathways, resulting in treatment-refractory CLL.  Our studies demonstrated that increased expression of DNA-dependent protein kinase (DNA- PK, which mediates non-homologous end joining) is also associated with shorter survival in CLL. 
 At the Northern Institute for Cancer Research, we have established a well characterised CLL biobank (currently n=160), for use in ex vivo assays. Our recent studies show that cells from patients with one ATM allele deleted and one mutated - rendering the CLL cells completely ATM deficient - are highly sensitised to fludarabine by the prototype DNA PK inhibitor (NU7441).  This offers potential for exploitation of "synthetic lethality" in ATM-defective CLL, using a DNA PK inhibitor in an analogous manner to the use of poly(ADP-ribose)polymerase inhibitors for breast or ovarian cancer with BRCA mutations. Of the 10-20% of CLL cases with del(11q), 40% carry ATM mutations on the second allele, and functional studies  to determine chemosensitivity and ATM activity can stratify these patients.
Together with AstraZeneca, we are developing DNA PK inhibitors suitable for clinical evaluation. The aim of this studentship is to undertake studies with novel DNA-PK inhibitors (including potential clinical candidates) to test the hypothesis that DNA-PK inhibition will selectively potentiate the cytotoxicity of DNA damaging agents, providing targeted therapy for ATM defective CLL patients.
 To achieve this, the student will use ATM function profiling to determine the ATM status of CLL cells isolated from patient samples. The student will be trained in basic molecular biology techniques and viability and apoptosis assays for use with primary CLL cells cultured ex vivo. Using these techniques, the student will test novel DNA-PK inhibitors and develop pharmacodynamic biomarkers for use in clinical trials. During a placement at AstraZeneca, the student will use state-of-the-art microarray technology to analyse the gene signature of response to DNA damage and DNA-PK inhibition in samples from del(11q) patients, and also investigate epigenetic regulation of ATM in CLL.
 
Depending on how you meet the MRC's eligibility criteria, you may be entitled to a full or a partial award. A full award covers tuition fees at the UK/EU rate and an annual stipend of £13,590.  A partial award covers fees at the UK/EU rate only.
 
You must complete the University's postgraduate application form. Select "Doctor of Philosophy (Medical Sciences) - Cancer Research" as the programme of study. Only mandatory fields need to be completed (no personal statement required) but you must attach a copy of your CV and a covering letter, quoting the title of the studentship and reference number CR051

Deadline: 08-04-2011

Contacts:

Email: herbie.newell@ncl.ac.uk

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