Background: Glioblastoma (GBM) is the most common and aggressive type of primary brain cancer, associated with extremely poor outcomes for patients (average length of survival ~12 months). Current treatments including tumour removal by surgical ‘debulking’ and adjuvant chemoradiotherapy can only eliminate the central tumour mass. Due to the brain-infiltrative, therapy-resistant, and stem cell-like biology of GBM tumours, there are currently no effective treatments that stop GBM progression and recurrence during/after therapy. While brain tumour recurrence varies patient-to-patient, tumour repopulation from residual cancer cells has a high metabolic energy demand. Therefore, pharmaceutical exploitation of promising metabolic targets is highly desirable.
Through a phenotypic drug discovery/target deconvolution approach, we established that chemical inhibition of the mitochondrial chaperonin HSPD1 (Hsp60), which has been implicated in cancer proliferation and apoptosis, causes selective bioenergetic exhaustion and death of patient derived GBM cells in vitro and in animal models. Subsequent studies (cryo-EM, photoaffinity labelling, structure-activity relationships) suggest that our lead compound KHS101 works through a mechanism unique to HSPD1 inhibitors: allosteric stabilisation of a conformational state that prevents protein-protein interactions of HSPD1.
As a next step towards translational drug development, we aim to develop patient-derived GBM cell models expressing inhibitor-resistant HSPD1 variants for genetic rescue experiments, the gold standard in pre-clinical target validation and a proven platform for new biological discovery with clinical impact.
Our objectives will be:
1. Identification of functional, inhibitor-resistant HSPD1 variants (genomic modification in GBM cells complemented by structure-guided protein design).
2. In vitro structural characterisation of inhibitor-resistant HSPD1 variants.
3. Functional characterisation of inhibitor-resistant HSPD1 variants in GBM models.
The project is interdisciplinary and involves the infrastructure and expertise of tumour biology (@SCBT_Research), chemical biology (@RSBon_Lab), and structural biology (@stemuench) labs. The project builds on recently published work, and you will use our protocols for molecular biology (mutagenesis, protein expression/purification, lentiviral expression), biochemical/cellular assays (such as HSPD1 enzymatic/refolding assays combined with GBM cell phenotyping) and cryoEM, complemented by CRISPR tiling. Through these approaches you will validate pharmacological inhibition of HSPD1 as a suitable target for an unmet clinical need. In addition to targeting GBM, the emerging tools and your expertise will enable the potential use of HSPD1 inhibition as a first-in-class treatment strategy for other HSPD1-dependent malignancies, including cancers of the breast, lung, prostate, pancreas, ovaries, liver, colon, and multiple myeloma.
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
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