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The road to personalised anticancer therapy : utilising the LAT-1 transporter as a selective means for iron deprivation (ref: SF18/APP/Veuger)

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Recent statistics show that 1:2 people in the UK will develop cancer during their life. Of particular interest are new therapeutics that potentially allow a specific focus on tumours that are aggressive, metastatic and associated with poor prognosis.
A PhD student at N.U. is synthesising metal chelators that protect neurons against oxidative damage. These compounds have molecular features that enable them to cross the blood brain barrier by making them substrates of LAT-1. The compounds contain powerful Fe3+ chelator groups, hydroxypyridinones.
Metal chelators are known to be promising therapeutic agents against some forms of cancer (disruption of metal homeostasis, disruption of ROS formation, iron deprivation). Non-targeted chelators of the hydroxypyridinone family are known to have anti-cancer properties. Moreover, LAT-1 is over-expressed in some forms of cancer. We hypothesise that our compounds could preferentially target these cancer cells, inhibit their proliferation and promote cell death. Our compounds are available (more are being made) and ready for screening against cancer cell lines. Strikingly, LAT-1 status is considered a novel biomarker for high grade malignancy in prostate cancer and preliminary data within our group using prostate cancer cell lines show a differential sensitivity between PC3 (more aggressive) and DU145 cells thus demonstrating an effect of these compounds on cell survival and death.
The first aim of this project will be to high throughput screen for cytotoxicity across a range of well characterised sets of cells derived from normal and cancerous cells. We will stratify according to LAT-1 status as well as confirm the mode of entry and mechanism of action of these drugs The second aim will be to screen other cell behaviours that alter in cancer progression. For example, we will use a combination of end point assays (eg. clonogenic, comet and caspase) with sophisticated and established kinetic real time analysis, xcelligence.

Eligibility and How to Apply:
Please note eligibility requirement:
• Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.
• Appropriate IELTS score, if required.

For further details of how to apply, entry requirements and the application form, see
https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

Please note: Applications should include a covering letter that includes a short summary (500 words max.) of a relevant piece of research that you have previously completed. Applications that do not include the advert reference (e.g. SF18/…) will not be considered.

Deadline for applications: 1st July 2019 for October 2019 start, or 1st December 2018 for March 2019 start
Start Date: October or March

Northumbria University takes pride in, and values, the quality and diversity of our staff. We welcome applications from all members of the community. The University holds an Athena SWAN Bronze award in recognition of our commitment to improving employment practices for the advancement of gender equality and is a member of the Euraxess network, which delivers information and support to professional researchers

Funding Notes

This studentship is only open to self-funding candidates. Self-funding candidates are expected to pay University fees and to provide their own living costs. University fee bands are shown at
View Website
Projects in Applied Sciences are typically costed at Band 3 or Band 4.

References

Jenkinson, S. E., Brown, L., Milburn, J. A., Smulders-Srinivasan, T, Veuger, S, Edwards, D. R. and Bass, R. Identification of novel peptide motifs in the serpin maspin that affect vascular smooth muscle cell function. (2017) Biochimica et Biophysica Acta - Molecular Cell Research, 1864 (2). 336-344.
Workman, D. Hunter, M. Dover, L and Tetard, D. Synthesis of novel Iron(III) chelators based on triaza macrocycle backbone and 1-hydroxy-2(H)-pyridin-2-one coordinating groups and their evaluation as antimicrobial agents. (2016) Journal of inorganic biochemistry. 160, 49-58

Workman, D ,Tsatsanis A , Lewis F , Boyle,J Mousadoust M, Hettiarachch N, Hunter M, Peers C, Tetard D and James A. Duce* Protection from neurodegeneration in the 6-hydroxydopamine (6-OHDA) model of Parkinson’s with novel 1-hydroxypyridin-2-one metal chelators. (2015) Metallomics ,7 ,867

Forgham, H, Johnson, D, Carter, N, Veuger, S and Carr-Wilkinson, J Stem Cell Markers in Neuroblastoma—An Emerging Role for LGR5. (2015) Frontiers in Cell and Developmental Biology, 3.
Hunter JE, Durkacz BW & Veuger SJ NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-. (2012) Oncogene 31; 251-264

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