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Developing nanoparticles to target neuroendocrine tumour for overcoming resistance to cancer treatment


   Faculty of Biology, Medicine and Health


About the Project

Many cancer patients having undergone local and systemic treatment eventually develop and die from the progression of distant metastasis associated with the relapse in primary tumour growth. Cell populations in hypoxic niches, including cancer stem cells (CSC), that are resistant to conventional chemo- and radiotherapy regimens are important contributors to the loss of control.

For survival, regulating pH in the tumour microenvironment is highly important for the metabolically active cancer cell. Hypoxia induces the overexpression of carbonic anhydrase isoform IX (CAIX) in order to regulate the tumour cell intracellular pH for promoting proliferation, adhesion, and malignant invasion. Resistant tumour cells and CSCs express high levels of hypoxia-induced carbonic anhydrase IX (CAIX). Targeting CAIX is regarded as a key approach to destroy the resistant cell populations. We previously found that CAIX inhibitors based on the sulfamate class are potent and selective inhibitors of cancer cell migration and some “hit compounds” were found to have anti-tumour/metastatic properties. 

These anticancer agents however suffered from low aqueous solubility and can have cytotoxic effect on healthy tissues. In parallel work gastrin releasing peptide (GRP) has been shown to promote growth of many neuroendocrine cancers including lung, pancreatic and prostate cancer. We have developed a novel penta-peptide derived from Substance P antagonist G (SPG), with much superior anti-tumour activity than the SPG, to target the GRPR receptor. The expression of carbonic anhydrase IX (CAIX) and gastrin-releasing peptide receptor (GRPR) is increased in such tumours and is linked to cancer growth and progression.

CAIX expression is associated with increased cell survival and migration whereas GRPR expression is associated with autocrine stimulation of cell growth. This link makes these proteins novel dual targets for potential anticancer therapies. This PhD project will involve studying effectiveness of simultaneously hitting both (GRPR and CAIX) targets to inhibit neuroendocrine tumour growth and aggressiveness with a view to developing a novel nanoparticle sized drug delivery system. 

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with previous laboratory experience are particularly encouraged to apply.

How To Apply

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 appropriate subject title.

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.

Equality, Diversity and Inclusion

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 https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/”


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

References

J Med Chem. 2012 Jun 14;55(11):5591-600. doi: 10.1021/jm300529u
RSC Adv., 2014,4, 10779-10790. DOI: 10.1039/C3RA44746D
Medchemcomm. 2017 Feb 17;8(3):551-558. doi: 10.1039/c6md00691d
Eur J Med Chem. 2017 Sep 8;137:221-232. doi: 10.1016/j.ejmech.2017.05.053
Int J Cancer. 2018 Jan 1;142(1):191-201. doi: 10.1002/ijc.31042

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