Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer
| العنوان: | Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer |
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| المؤلفون: | Neel Patel, Lisa Ayers, Ioannis Roxanis, Luc Bidaut, Fredrik Karpe, Simon Lord, Mei Lin Ah-See, Christos E. Zois, Cameron Snell, Pankaj G. Roy, Christian Frezza, Leticia Campo, Adrian L. Harris, Francesca M. Buffa, Kevin M. Bradley, Ruth English, Fergus V. Gleeson, Tim James, R F Adams, Tom Metcalf, Syed Haider, Anand Sharma, Daniel R. McGowan, Dan Liu, Eugene J. Teoh, John D. Fenwick, Michael Pollak, Edoardo Gaude, Wei Chen Cheng, Simon Wigfield, Alastair M. Thompson |
| المساهمون: | Frezza, Christian [0000-0002-3293-7397], Apollo - University of Cambridge Repository |
| المصدر: | CELL METABOLISM Cell Metabolism |
| بيانات النشر: | Elsevier BV, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, A300 Clinical Medicine, positron emission tomography, endocrine system diseases, Physiology, B210 Pharmacology, cancer metabolism, Mitochondrion, Transcriptome, 0302 clinical medicine, Positron Emission Tomography Computed Tomography, G150 Mathematical Modelling, B100 Anatomy, Physiology and Pathology, C130 Cell Biology, Middle Aged, metabolomics, Metformin, 3. Good health, Mitochondria, B800 Medical Technology, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Female, Metabolic Networks and Pathways, medicine.drug, Adult, Antineoplastic Agents, Breast Neoplasms, 03 medical and health sciences, Metabolomics, Breast cancer, B132 Pathobiology, medicine, gene expression profiling, Humans, Hypoglycemic Agents, Molecular Biology, Aged, business.industry, Cell Biology, clinical study, medicine.disease, Gene expression profiling, Clinical trial, 030104 developmental biology, Glucose, Cancer research, C100 Biology, business, Flux (metabolism) |
| الوصف: | Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect. |
| وصف الملف: | application/pdf |
| تدمد: | 1550-4131 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::75a168f8387e5f05dbe5abffbe69c6fc https://www.repository.cam.ac.uk/handle/1810/285637 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....75a168f8387e5f05dbe5abffbe69c6fc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15504131 |
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