Preclinical validation of a mitochondrial chaperonin as a target for the treatment of brain cancer

点击翻译按钮获取中文摘要

Background: Glioblastoma (GBM) is the most common and aggressive type of primary brain cancer, associated with extremely poor outcomes for patients. Current treatments including tumour removal by surgical 'debulking' and adjuvant chemoradiotherapy can only eliminate the central tumour mass. Dure to the brain-infiltrative, therapy-resistant and stem cell-like neology of GBM tumours, there are currently no effective treatments that stop GBM progression and recurrence during/ after therapy. While brain tumour recurrence varies from 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 which has been implicated in cancer proliferation and apoptosis, causes selective bioenergetic exhaustion and death if patient derived GBM cells in vitro and in animal models. Subsequent studies 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 validation and a proven platform for new biological clinical target validation and a proven platform for new biological discovery with clinical impact.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 GB cells complemented by structure-guided protein design)2. In vitro structural characterisation of inhibitor resistant HSPD1 variants3. Functional characterisation of inhibitor-resistant HSPD1 variants in GBM modelsThe project is interdisciplinary and involves infrastructure and expertise of tumour biology, chemical biology, and structural biology labs.The project builds on a 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 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-dependant malignancies, including cancers of the breast, lung, prostate, pancreas, ovaries, liver, colon, and multiple myeloma.