MRC DiMeN Doctoral Training Partnership: Developing novel quantitative imaging methods for target validation in experimental models of glioblastoma brain cancer

Description

Glioblastoma (GBM) is the most aggressive form of brain tumour. Despite surgical resection and chemo-radiation therapy, survival remains dismal as the tumour often recurs, which is highly resistant to therapies. The secondary supervisor has identified a candidate target SLC6A6, a gene encoding taurine transporter TauT that is significantly upregulated in resistant tumours. Preliminary data confirms that manipulation of SLC6A6 alters treatment sensitivity and implicates a role for hypoxia and angiogenesis, which requires mechanistic assessment in a vascularised model. Our group is developing a novel chick embryo model of GBM as it replicates the tumour-host vascular environment observed in human GBM. This project capitalizes on ongoing collaboration between the supervisors which aims to build relevant GBM models to mimic human tumours to expedite clinical translation.

Novelty

SLC6A6 is a novel drug target that has been linked with treatment resistance in multiple cancers but not in GBM. Although MRI is used in the clinic, these methods are generally qualitative and have not been developed for quantitative analysis of the chick embryo model at the microstructural level needed for this model.

Experimental Approach

(1)   Development of the knockdown tumour model in the chick embryo model. This would involve injection of cells in the fertilised hen egg, longitudinal imaging to assess tumour growth and validation with histology

(2)   Development of high-resolution MRI methods to quantitatively assess tumour associated vasculature – specifically development of MR angiographic methods.

(3)   Quantitative analysis of the imaging data to assess vessel diameter, number of vessels feeding the tumour, tumour volume and changes due to treatment

(4)   Development of quantitative MRS methods to assess tumour metabolism in ovo and changes therein as potential markers of treatment response.

Training Available

The primary supervisor has an expertise in the development of quantitative imaging methods for assessing treatment response in rodent models of GBM. He will provide training in multi-modal preclinical imaging techniques. The secondary supervisor will house the student providing training in experimental and computational GBM biology. The student will bring these skills back to Liverpool, and the secondary supervisor could participate in DiMEN training as an external speaker. The tertiary supervisor has expertise in studying ubiquitin biology through molecular, cellular and biochemical techniques and is leading the program of developing the chick embryo model as an alternative to animal models in cancer research. 

 This cross-departmental and cross institutional collaboration brings complementary expertise in several areas including neuro-imaging, neuro-biology and behavioural biology. The collective backgrounds of the supervisors provide complementary expertise in tackling the complex interplay between genetic mutation, tumour microenvironment and metabolism and the project will open new avenues for scientific collaboration on both preclinical and clinical imaging technologies towards better understanding of disease. The student will work in the University of Liverpool Preclinical Imaging facility, to characterise the GBM model using cutting edge imaging assays.

Prof Harish Poptani: https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/staff/harish-poptani/

Dr Lucy Stead: https://medicinehealth.leeds.ac.uk/medicine/staff/789/dr-lucy-stead

Prof. Judy Coulson: https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/staff/judy-coulson/

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website: https://www.dimen.org.uk/how-to-apply