Glioblastoma (short: 'GBM') is the most common and aggressive type of primary brain cancer, associated with extremely poor outcomes for patients. Current treatments (surgical tumour debulking followed by chemo- and radiotherapy) can only eliminate the central tumour mass and there are currently no effective treatments that stop GBM progression during/after therapy. While brain tumour recurrence varies on a patient-to-patient basis, tumour repopulation from residual cancer cells has a high metabolic energy demand. Therefore, pharmaceutical exploitation of promising and/or newly- identified metabolic targets is highly desirable.
We previously identified a small molecule (KHS101) that disrupts the energy metabolism of patient-derived GBM cells, but not normal brain cells. Through this mechanism, KHS101 causes selective bioenergetic exhaustion and death of GBM cells in vitro and in animal models (Polson et al., 2018). We discovered that KHS101 works by inhibition of the mitochondrial chaperonin HSPD1 (Hsp60), and that GBM cells depend on HSPD1 for maintaining the correct folding of mitochondrial proteins required for energy metabolism (Polson et al., 2018).
To enable HSPD1-targeted drug development, we urgently need to unravel the HSPD1 inhibition mechanism of early drug leads such as KHS101, the only reported HSPD1-binding small molecule with anti-GBM activity in vivo. Based on our published (Klebl et al., 2020) and unpublished data, we hypothesise that KHS101 inhibits HSPD1 function through a novel molecular mechanism.
In this project, you will validate and refine our current structural model through a combination of structural/biophysical techniques such as cryo-electron microscopy, mass spectrometry and molecular interaction analysis. You will then use the refined structural model to engineer variants of HPSD1 that retain function in GBM cells, but are resistant to KHS101 (and related inhibitors). You will use these HSPD1 variants in cellular assays to demonstrate that HSPD1 is an actionable drug target for the treatment of GBM.
The fundamental discoveries emerging from this project will underpin ongoing anti-GBM drug discovery work. In addition, the new tools and expertise will be instrumental in the validation of HSPD1 inhibition as a potential strategy for the treatment of other HSPD1-dependent malignancies, including cancers of the breast, lung, prostate, pancreas, ovaries, liver, colon, and multiple myeloma.
This project will be supervised by Dr Robin Bon (https://medicinehealth.leeds.ac.uk/medicine/staff/1194/dr-robin-s-bon; @RSBon_Lab), Dr Heiko Wurdak (https://medicinehealth.leeds.ac.uk/medicine/staff/905/dr-heiko-wurdak; @scbt_research) and Dr Stephen Muench (https://biologicalsciences.leeds.ac.uk/school-biomedical-sciences/staff/116/dr-stephen-muench; @stemuench). You will make use of established protocols for molecular biology (mutagenesis, protein expression/purification, lentiviral expression), biochemical/cellular assays (HSPD1 foldase assays, GBM cell phenotyping) and structural biology (cryoEM, molecular modelling). Full training and support for all these techniques will be provided in the labs of the supervisors, taking advantage of our established training programs such as the Wellcome trust/MRC funded cryoEM training program.
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: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
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