Residual breast cancer metabolic phenotype after docetaxel treatment

[摘要] Despite improvements in early diagnosis and prevention, late stage breast cancer is often incurable due to metastasis, tumour relapse, resistance and incomplete response to treatments. Metabolic reprogramming has been recognised as a critical element for cancer cells to grow under hostile conditions and this is likely to contribute towards resistance against chemotherapeutics. This thesis therefore aimed at deciphering the metabolic phenotype of residual breast cancer which survived docetaxel treatment, \(in\) \(vitro\) and \(in\) \(vivo\), quantifying polar metabolite levels and conducting pathway tracing and metabolic flux analysis using stable isotope (\(^{13}\)C) labelled tracers. \(In\) \(vitro\) residual cells presented a hypermetabolic phenotype characterised by significant accumulation of essential and non-essential amino acids, together with an elicited Warburg effect and an increased antioxidant response based on glutathione production, while in growth arrest. A method to carry out \(in\) \(vivo\) tracer-based metabolic studies was successfully developed using a breast cancer mouse model. Although the metabolite accumulation outlined \(in\) \(vitro\) was not observed \(in\) \(vivo\), a protective phenotype against oxidative stress was supported by increased flux through the oxidative branch of the pentose phosphate pathway. In conclusion, this thesis demonstrated that metabolic phenotyping is a valid approach to uncover key metabolic alterations in residual tumours both \(in\) \(vitro\) and \(in\) \(vivo\), and could be further exploited to design personalised treatments aimed at restoring sensitivity to therapies.

[发布机构] University:University of Birmingham;Department:Institute of Cancer and Genomic Sciences

[关键词] R Medicine;RC Internal medicine;RC0254 Neoplasms. Tumors. Oncology (including Cancer)