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Developing inhibitors of Rac1b as a potential novel drug against breast cancer stem cells


Project Description

Breast cancer is the most common cancer in the UK with a lifetime risk of 1-in-8 for women and accounts for 12,000 deaths annually. Although current treatment options can significantly reduce the tumour burden in breast cancer patients, tumour relapse is a frequently occurring problem. At the core of this clinical problem are the breast cancer stem cells (Br-CSCs), a small fraction of cells within tumours that have stem cell features. Br-CSCs are responsible not only for primary tumour formation, but also for metastasis, therapy resistance and tumour recurrence. Therefore, a true cure for breast cancer can only be achieved by developing novel therapies that can eradicate the Br-CSCs.

Rac1b is a constitutively active splice variant of the small GTPase Rac1. We have recently shown that Rac1b is expressed specifically in ER+ breast cancer cells and its function is involved in the regulation of breast cancer stem cells’ (Br-CSCs) plasticity and chemoresistance. Its genetic deletion in ER+ human breast cancer cell lines leads to an increased chemosensitivity and abolishes their in vivo tumour formation capacity. These results suggest that Rac1b is a promising molecular target against which to devise novel therapies for breast cancer. These therapies could thus eradicate Br-CSCs, tackling the disease at the very apex of the tumour cell ontogeny.

The aim of this cross-disciplinary project is to develop specific inhibitors of the Rac1b protein. To this end, we will computationally investigate the structure, dynamics and interactions of Rac1b compared to Rac1. Accordingly, we will design, synthesize and test chemical compounds for selective Rac1b inhibition, which will then be tested in human breast cancer cell lines as well as in small animal models of breast cancer.

The candidate should have an academic scientific training, culminating in an M.Sc in a relevant subject (e.g. molecular/cellular/cancer biology, computational biology, or chemistry). Previous experience in working with computational simulation programmes, cell cultures and animal models would be preferable.

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 PhD Drug Design, Development and Delivery.

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 http://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). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

Fees can be found here K:\FBMH Doctoral Academy\DA Reference Library - Policy and Procedures\Fees

References

Integrin-Rac signalling for mammary epithelial stem cell self-renewal. S. Olabi, A. Ucar et al. Breast Cancer Res. 2018, 20, 128.

The requirement of integrins for breast epithelial proliferation. P. Moreno-Layseca, A. Ucar et al. Eur. J. Cell. Biol. 2017, 96, 227.

Identification of rare Lewis oligosaccharide conformers in aqueous solution using enhanced sampling molecular dynamics. I Alibay, K. K. Burusco, N. J. Bruce, R. A. Bryce. J. Phys. Chem. B, 2018, 122, 2462-2474.

New boron based inhibitors of the NLRP3 inflammasome. A. G. Baldwin, J. Rivers-Auty, M. J. D. Daniels, C. S. White, C. H. Schwalbe, T. Schilling, H. Hammadi, P. Jaiyong, N. G. Spencer, H. England, N. Luheshi, M. Kadirvel, C. B. Lawrence, N. J. Rothwell, M. K. Harte, R. A. Bryce, S. M. Allan, C. Eder, S. Freeman and D. Brough. Cell Chem. Biol. 2017, 24, 1 – 15.

Analysis of enoyl acyl carrier protein reductase structure and interactions yield an efficient virtual screening approach and suggest a potential allosteric site. M. A. Ghattas, R. A. Mansour, N. Atatreh and R. A. Bryce. Chem. Biol. Drug Des. 2016, 87, 131–142.

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