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Evaluating novel therapeutic strategies to target tumour metastases


   Faculty of Biology, Medicine and Health

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Metastases are a frequently incurable and devastating outcome for many cancer patients with advanced disease. Clinical evidence illustrates that different primary tumours metastasise to preferential sites - a phenomenon that underpinned Paget’s “seed and soil” hypothesis, proposing that specific cancer ”seeds” proliferate well in specific secondary site “soils”. The mechanisms driving targeted metastases are complex and involve changes in both cells within the primary tumour and at the metastatic site. The latter generates a permissive “niche” for the subsequent influx and growth of cancer cells. Oncogenic signalling pathway activation, metabolic phenotype, physiological conditions and tumour immune composition are amongst some of the many characteristics that have the potential to influence the propensity of a tumour cell to metastasise. Further they can be involved in regulating the signalling cascades and processes that can also impact the secondary site “niche”. Common to all of these tumour–related characteristics is the fact that they have been recognised as therapeutic targets, and novel drugs have been developed against key aspects within each area. How these could be used alone or in combination, in a rationale manner to influence metastases is not fully known. This project aims to use complementary in vitro and in vivo approaches to evaluate the ability of novel therapeutic approaches to modify cancer metastasise and improve overall therapy outcome. The project will adopt cell and molecular techniques to evaluate therapeutic response and use co-culture systems to model interaction between specific cell types that influence metastasis. Approaches that look promising from in vitro studies will be taken forward into well-validated in vivo models of metastases, allowing efficacy and biological response to be monitored. The potential outcomes from this research will be a greater understanding of the biological drivers of metastasis and an initial evaluation of therapeutic strategies with the potential to inhibit this process.

 1.     Candidates are expected to hold (or be about to obtain) a first class honours degree (or equivalent) in a Biosciences or a related subject.  Candidates with experience in Cancer Biology, Biochemistry and Pharmacology are encouraged to apply.

 2.     For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the PhD title.

3.     For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit www.internationalphd.manchester.ac.uk


Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

1. Green D, Eyre H, Singh A, Taylor JT, Chu J, Jeys L, Sumathi V, Coonar A, Rassl D, Babur M, Forster D, Alzabin S, Ponthan F, McMahon A, Bigger B, Reekie T, Kassiou M, Williams K, Dalmay T, Fraser WD, Finegan KG. Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer. Oncogene. 2020 Aug;39(33):5553-5569. doi: 10.1038/s41388-020-1379-0.
2. 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. doi: 10.1002/ijc.31042. Epub 2017 Oct 3. *shared senior authorship
3. Searle EJ, Telfer BA, Mukherjee D, Forster DM, Davies BR, Williams KJ*, Stratford IJ*, Illidge TM*. Akt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment. EMBO Mol Med. 2017 Dec;9(12):1646-1659. doi: 10.15252/emmm.201707767. *shared senior authorship
4. Burrows N, Williams J, Telfer BA, Resch J, Valentine HR, Fitzmaurice RJ, Eustace A, Irlam J, Rowling EJ, Hoang-Vu C, West CM, Brabant G, Williams KJ. Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas. Oncotarget. 2016 Sep 27;7(39):63106-63123. doi: 10.18632/oncotarget.11056.
5. Giurisato E, Xu Q, Lonardi S, et al. Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition. Proc Natl Acad Sci U S A. 2018;115(12):E2801-E2810. doi:10.1073/pnas.1707929115

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