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Carbonic anhydrases as a molecular target to destroy the therapy resistant cancer stem cells in small cell lung cancer (RDF19/HLS/AS/GIELING)

  • Full or part time
  • Application Deadline
    Friday, January 25, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Cancer treatment is often compromised by populations of cells which are resistant to the therapy. These cells possess stemness properties and are therefore often regarded to be the cancer stem cells (CSCs). They reside in hypoxic niches which provides the ideal environmental conditions for them to sustain harsh treatment regimens. Many reports indicate that the involvement of Hypoxia-Inducible Factor 1 (HIF1), and genes regulated by this pathway, is critical in cancer cell survival. Our focus has been on the Carbonic Anhydrase IX gene (CA9), encoding an enzyme essential in regulation of the intracellular pH and required for cancer cell survival. The enzymatic activity of this protein in cancer cells is effectively reduced with isoform specific CA inhibitors of the sulfamate and sulphonamide classes. These compounds have been shown to exert anticancer effects including reducing cell growth and increasing cell death, and to enhance the effectiveness of existing therapies. The objective of the proposed project is to determine the therapeutic effectiveness of isoform IX specific CA inhibitors against CSCs in an in vitro model of human lung cancer consisting of i) Cisplatin-sensitive Small Cell Lung Cancer cells (DMS79); ii) Cisplatin-sensitive Non-Small Cell Lung Cancer cells (A549) and iii) normal lung fibroblasts (MRC-5). So far, our results have shown that our CA IX inhibitors enhance cell death in hypoxic SCLC cells. This project will aim to address the molecular mechanism by which these inhibitors target hypoxic SCLC cells and whether the pool of CSCs is effectively reduced by this treatment.

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.
• Applicants cannot apply for this funding if currently engaged in Doctoral study at Northumbria or elsewhere.

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: All applications must include a covering letter (up to 1000 words maximum) including why you are interested in this PhD, a summary of the relevant experience you can bring to this project and of your understanding of this subject area with relevant references (beyond the information already provided in the advert).

Deadline for applications: Friday 25 January 2019

Start Date: 1 October 2019

Northumbria University is an equal opportunities provider and in welcoming applications for studentships from all sectors of the community we strongly encourage applications from women and under-represented groups.

Faculty: Health and Life Sciences
Department: Applied Sciences
Principal Supervisor: Dr Roben Gieling, Senior Lecturer in Cellular Pathology

Funding Notes

The studentship is available to Home/EU students where a full stipend, paid for three years at RCUK rates (for 2018/19, this is £14,777 pa) and full fees.

References

The following original papers underpin the therapeutic potential of isoform specific carbonic anhydrase inhibitors targeting the tumour associated isoform IX and in particular in SCLC.

1- Bryant JL, Gieling RG, Meredith SL, Allen TJ, Walker L, Telfer BA, Supuran CT, Williams KJ, White A. Novel carbonic anhydrase IX-targeted therapy enhances the anti-tumour effects of cisplatin in small cell lung cancer. Int J Cancer. 2018 Jan 1; 142(1):191-201.

2- van Kuijk SJ, Gieling RG, Niemans R, Lieuwes NG, Biemans R, Telfer BA, Haenen GR, Yaromina A, Lambin P, Dubois LJ, Williams KJ. The Sulfamate Small Molecule CA IX Inhibitor S4 Modulates Doxorubicin Efficacy. PLoS One. 2016 Aug 11; 11(8): e0161040.

3- Pettersen EO, Ebbesen P, Gieling RG, et al. Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium. J Enzyme Inhib Med Chem. 2015;30(5):689-721.

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