A5014028774- Metabolomics and Mass Spectrometry Studies
- Cancer, Hypoxia, and Metabolism
- Cancer Genomics and Diagnostics
- Multiple Myeloma Research and Treatments
- Acute Myeloid Leukemia Research
- Enzyme Structure and Function
- Glioma Diagnosis and Treatment
- Medical Imaging Techniques and Applications
- Mass Spectrometry Techniques and Applications
- DNA Repair Mechanisms
- Advanced MRI Techniques and Applications
University of Oxford
2019-2022
University of Oslo
2019
Abstract Altered central carbon metabolism is a hallmark of many diseases including diabetes, obesity, heart disease and cancer. Identifying metabolic changes will open opportunities for better understanding aetiological processes identifying new diagnostic, prognostic, therapeutic targets. Comprehensive robust analysis primary pathways in cells, tissues bio-fluids, remains technically challenging. We report on the development validation highly reproducible untargeted method using...
Abstract Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment acute myeloid leukaemia (AML). Resistance to ivosidenib due a second site mutation IDH1 R132C, leading R132C/S280F, has emerged. We describe biochemical, crystallographic, cellular studies on R132C/S280F R132H/S280F variants that inform mechanism second-site resistance, which involves both modulation binding at dimer-interface alteration kinetic properties, enable...
Abstract Cancer linked isocitrate dehydrogenase (IDH) 1 variants, notably R132H IDH1, manifest a ‘gain-of-function’ to reduce 2-oxoglutarate 2-hydroxyglutarate. High-throughput screens have enabled clinically useful IDH1 inhibitors, mostly allosteric binders at the dimer interface. We report investigations on roles of divalent metal ions in IDH substrate and inhibitor binding that rationalise this observation. Mg 2+ /Mn enhance wt but with former manifesting lower K M s. The isocitrate-Mg...
Glioblastoma is the most common and malignant brain tumor, current therapies confer only modest survival benefits. A major obstacle our ability to monitor treatment effect on tumors. Current imaging modalities are ambiguous, repeated biopsies not encouraged. To scout for markers of response, we used NMR spectroscopy study effects a survivin inhibitor metabolome primary glioblastoma cancer stem cells. Applying high resolution (1H resonance frequency: 800.03 MHz) just 3 million cells per...