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Tyrosine kinase inhibitors conjugated tumour targeting dyes for the treatment of glioblastoma.


Project Description

Glioblastoma (GBM) remains a lethal and difficult to treat cancer with a dismal outcome. Although we have a better understanding of the disease progression, a concurrent increase in therapeutic intervention is lagging. Multiple factors such as tumour heterogeneity, dysregulation of various pathways, and treatment-resistant cells have contributed to the failure of many single-agent therapies. The inability of current chemotherapy agents to cross the BBB and the lack of tumour targeting agents that lead to toxicity have also made treatment of GBM a conundrum. Through this project, we propose to develop drug-dye conjugates that have the potential to cross the BBB and target tumours with higher specificity. Our published work has shown, for the first time, that combining a GBM-selective fluorescent molecule (HMCD) to known TKIs, resulted in enhanced cytotoxicity and cytostatic effect on patient-derived GBM cell lines. This project aims to further develop and test more novel compounds on patient-derived TMZ- and radiation-resistant GBM cell lines in an attempt to best recapitulate the treatment conditions seen in the clinic. Mechanistic studies utilising in vitro human BBB-GBM models will be undertaken to delineate the mode of action and transport of these conjugates. The data obtained from this study could be used to further design molecules to overcome treatment-resistance and give insight into improving the efficacy of TKIs in the treatment of GBM and other brain cancers. With current treatments only increasing the patient survival by a few months without much improvement in the quality of life, we hope that a different approach, such as the one proposed in this project, might lead to better treatment outcomes.

Our group has shown that appending an anaplastic lymphoma kinase (ALK) inhibitor such as Crizotinib to heptamethine cyanine dyes dramatically improves the antiproliferative activity of Crizotinib in patient-derived GBM cell lines. Similar drug dye conjugates are being explored to see their effect on Temolozomide resistant patient-derived GBM cell lines.
We are currently looking for enthusiastic PhD students to join this exciting project. The prospective student will be able to hone their synthetic medicinal chemistry skills in a modern drug discovery laboratory which has so far brought 12 drug candidates to clinical trial. The student is expected to have courses in synthetic organic chemistry during their undergraduate/ honours/master’s programme. Laboratory experience in synthetic/medicinal chemistry is desirable.

Eligibility: Applicants must have completed a postgraduate bachelors (honours) degree with first class or second class (division 1) honours, or a masters degree with first class or second class (division 1) honours in Chemistry. In addition you completed a significant research project, dissertation or thesis, at university level.

Grades or marks achieved at other institutions are given a Grade Point Equivalent (GPE) on the University’s 0-9 grading scale. If you have overseas qualifications you will typically need a GPE of 5.5 or over 8.0 to be eligible for a University of Auckland Doctoral Scholarship. We highly recommend that you calculate your GPE before applying. To view an indication of your GPE use our GPE calculator: https://www.gpecalculator.auckland.ac.nz

Additional information about the University of Auckland Doctoral Entry requirements can be found here:
https://www.auckland.ac.nz/en/study/applications-and-admissions/entry-requirements/postgraduate-entry-requirements/doctoral-entry-requirements.html

Funding Notes

Scholarships: For information relating to Scholarships from the University and possibly in conjunction with your home country, please see the following link
View Website

Fees: If you are a new international PhD student, you will pay the same annual tuition fee as New Zealand PhD students. The 2019 PhD tuition fee is NZ$7,108.80 per annum. In additional to the tuition fee, there is a Student Services Fee estimated at $847.20 for full-time study.

References

1. Choi, P. J.; Cooper, E.; Schweder, P.; Mee, E.; Faull, R.; Denny, W. A.; Dragunow, M.; Park, T. I.; Jose, J., The synthesis of a novel Crizotinib heptamethine cyanine dye conjugate that potentiates the cytostatic and cytotoxic effects of Crizotinib in patient-derived glioblastoma cell lines. Bioorg Med Chem Lett 2019, 29, 2617-2621.
2. Usama, S. M.; Zhao, B.; Burgess, K., A Near-IR Fluorescent Dasatinib Derivative That Localizes in Cancer Cells. Bioconjug Chem 2019, 30, 1175-1181.
3. Choi, P.; Noguchi, K.; Ishiyama, M.; Denny, W. A.; Jose, J., A mitochondria-selective near-infrared-emitting fluorescent dye for cellular imaging studies. Bioorg Med Chem Lett 2018, 28, 2013-2017.
4. Usama, S. M.; Jiang, Z.; Pflug, K.; Sitcheran, R.; Burgess, K., Conjugation of Dasatinib with MHI-148 Has a Significant Advantageous Effect in Viability Assays for Glioblastoma Cells. ChemMedChem 2019.

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