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  Redeploying Rucaparib: Understanding the role of PARP inhibitors in inflammation and cellular bioenergetics. A mechanism to overcome apoptosis resistance in cancer? (ref: SF22/HLS/APP/WALDEN)


   Faculty of Health and Life Sciences

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  Dr H Walden  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Inflammation in cancer is a double-edged sword. Acute inflammation is essential for the elimination of pathogens and also plays a role in eradicating cancerous cells with many modern cancer treatments designed to take advantage of these immune mechanisms. Chronic inflammation occurs when acute inflammation cannot be resolved or when a disease has a more insidious onset. The powerful mechanisms of chronic inflammation can have multiple negative effects and are associated with both the development and exacerbation of several diseases including cancer.

Poly (ADP-ribose) polymerases (PARPs) are important proteins in a wide range of biological mechanisms. PARP1 is key in both DNA repair and the regulation of inflammatory processes and inhibition of these processes has been shown to be beneficial in cancer therapy.  Therapeutic inhibition of PARP1 therefore represents an attractive target for cancer therapy. PARP inhibitors (PARPi) have received huge attention in oncology over recent years. They are FDA approved for use in BRCA1/2 defective breast and ovarian cancers with absent or dysfunctional homologous recombination repair function. This project builds on novel pilot data demonstrating a novel role of PARP inhibitors disrupting cancer cell bioenergetics.

Our data demonstrates that prostate cell lines, subject to low doses of one such PARPi (Rucaparib), yielded increased cell proliferation by tetrazolium salt assay. Paradoxically, protein content by Sulforhodamine B and nuclear morphology by epifluorescence, indicated cell death via apoptosis. Similar results have been shown in several studies using various cancer cell lines, and some conclude that conflicting results are due to a tetrazolium salt assay-based anomaly. We hypothesise that “increased proliferation” at low doses of Rucaparib likely identifies a metabolic switch from aerobic glycolysis to oxidative phosphorylation. Recent literature has shown that PARP-1 inhibition facilitates upregulated histone deacetylase sirtuin1 activity, via increased nicotinamide adenine dinucleotide (NAD+) availability, consequently culminating in altered mitochondrial bioenergetics.

In this project we aim to increase our understanding of the potential anti-inflammatory effect of Rucaparib which will be investigated in a number of cell culture based assays. This project will also examine further the effect of Rucaparib on cellular bioenergetics, using a number of in-house assays to conclusively link Rucaparib mediated apoptosis, SIRT1 activity and apoptosis in both primary and relevant cancer cell lines. Additionally, the Agilent Seahorse assay system will be utilised to develop novel assays, which we hypothesise, will demonstrate a use for PARP inhibitors, beyond BRCA1/2 mutations, in altering deregulated cellular bioenergetics and overcoming apoptosis resistance; two hallmarks of cancer.

The successful candidate will work with Dr Walden and Dr Veuger and join an established group within the Translational Biosciences Research Group at Northumbria University joining a team of three PhD students working in related areas.

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)

•      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: 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). Applications that do not include the advert reference (e.g. SF22/…) will not be considered.

 

Deadline for applications: Ongoing

Start Date: 1st October and 1st March are the standard cohort start dates each year.

Northumbria University is committed to creating an inclusive culture where we take pride in, and value, the diversity of our doctoral students. We encourage and welcome applications from all members of the community. The University hold a bronze Athena Swan award in recognition of our commitment to advancing gender equality, we are a Disability Confident Employer, a member of the Race Equality Charter and are participating in the Stonewall Diversity Champion Programme. We also hold the HR Excellence in Research award for implementing the concordat supporting the career development of researchers.

Informal enquiries to Dr Hannah Walden ([Email Address Removed])

Biological Sciences (4)

Funding Notes

This project is fully self-funded and available to applicants worldwide. Tuition fees will depend on the running cost of the individual project, in line with University fee bands found at https://www.northumbria.ac.uk/study-at-northumbria/fees-funding/. The fee will be discussed and agreed at interview stage.
Please note: to be classed as a Home student, candidates must meet the following criteria:
Be a UK National (meeting residency requirements), or
have settled status, or
have pre-settled status (meeting residency requirements), or
have indefinite leave to remain or enter.
If a candidate does not meet the criteria above, they would be classed as an International student.

References

Abdelaal, G., Carter, A., Panagiotidis, M., Tetard, D., Veuger, S Novel iron chelator SK4 demonstrates cytotoxicity in a range of tumour derived cell lines. (2022), Frontiers in Molecular Biosciences 9:1005092
Kyriakou, S., Cheung, W., Mantso, T., Mitsiogianni, M., Anestopoulos, I., Veuger, S., Trafalis, D., Franco, R., Pappa, A., Tetard, D., Panayiotidis, M A novel methylated analogue of L-Mimosine exerts its therapeutic potency through ROS production and ceramide-induced apoptosis in malignant melanoma. (2021), In: Investigational New Drugs 39 (4) 971-986
Kyriakou, S., Mitsiogianni, M., Mantso, T., Cheung, W., Todryk, S., Veuger, S., Pappa, A., Tetard, D., Panagiotidis, M Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma. (2020), Investigational New Drugs 38(3) 621-33

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