Many cancer patients who have had 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. Resistant tumour cells and CSCs express high levels of hypoxia-induced carbonic anhydrase IX (CA IX). Targeting CA IX is regarded as a key approach to destroy the resistant cell populations.
With the elucidation of the crystal structure of carbonic anhydrase, small molecular inhibitors for CA IX were developed. We previously found that these CA IX inhibitors based on the sulfamate class are potent and selective inhibitors of cancer cell migration and some “hit compounds” like S4 are very effective preclinical as anti-tumour/metastatic compounds. CA IX catalyses the hydration of carbon dioxide to bicarbonate and protons. Biologically, CA IX plays an active role in tumour physiology principally through its catalytic activity-mediated control of pH and cell adhesion/migration. Hypoxia-inducible factor 1 (HIF-1) signalling is the main driver behind the expression of CA IX. CA IX helps to retain a relatively neutral pH in tumour cells allowing tumour cells to survive.
This PhD project will involve the validation of CA IX inhibitors to endorse the effectiveness in inhibiting tumour growth and aggressiveness in in vitro assays. Lead compound S4 and any water soluble analogues will be encapsulated in nanosized lipid vesicles to enhance the tumour uptake improving the bioavailability to the primary tumour and/or metastasis.
The biochemistry and formulation aspects of the project will provide extensive training in several techniques including HPLC, fluorescence labelling, mass spectrometry, high pressure extrusion, microencapsulation and dynamic light scattering. The biological validation will involve training in a variety of cell culture techniques including monolayer and 3D-spheroid cultures, biochemical assays (western blotting, enzyme-linked bioassay (ELISA), MTT proliferation assay) and immunocytochemistry.
This project will be conducted within Manchester Pharmacy School, recently confirmed as the leading UK research base for Pharmacy following the 2014 Research Excellence Framework.
Candidates are expected to hold an MPharm, or BSc in chemical/biological sciences or medicinal chemistry. A Masters degree in a similar area would be an advantage. Candidates should have prior experience of cell culture and biochemical techniques (western blotting, Elisa, FACS) and/or experience in bioconjugation chemistry with interest in nanoparticle formulations.
This 3-year full-time PhD is open to candidates able to provide evidence of self-arranged funding/sponsorship. Annual fee rates for this project, due to commence from January 2016 onwards, are:
*UK/EU nationals: £14,000
Non-EU nationals: £26,500
Please direct applications in the following format to Dr Harmesh Aojula ([email protected]
• Academic CV
• Official academic transcripts
• Contact details for two suitable referees
• A personal statement (750 words maximum) outlining your suitability for the study, what you hope to achieve from the PhD and your research experience to date
• Evidence of funding.
Any enquiries relating to the project and/or suitability should be directed to Dr Aojula. Applications are invited on an on-going basis but early expression of interest is encouraged.
Gieling RG, et al. Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts. J Med Chem. 2012 Jun 14;55(11):5591-600
Gieling RG, Williams KJ. Carbonic anhydrase IX as a target for metastatic disease. Bioorg Med Chem. 2013 Mar 15;21(6):1470-6
Jennifer L. Bryant, et al. Inhibiting carbonic anhydrase IX targets hypoxic small cell lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl): Abstract nr 4980. Doi:10.1158/1538-7445.AM2014-4980
Offerman SC, et al. Ability of co-administered peptide liposome nanoparticles to exploit tumour acidity for drug delivery. RSC Adv., 2014,4, 10779-10790. DOI: 10.1039/C3RA44746D