Targeting cancer cell metabolism as a therapeutic strategy

Chaneton, Barbara Julieta (2014) Targeting cancer cell metabolism as a therapeutic strategy. PhD thesis, University of Glasgow.

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Abstract

In the past 15 years the field of cancer metabolism has burst providing vast quantities of information regarding the metabolic adaptations found in cancer cells and offering promising hints for the development of therapies that target metabolic features of cancer cells. By making use of the powerful combination of metabolomics and 13C-labelled metabolite tracing we have contributed to the field by identifying a mitochondrial enzymatic cascade crucial for oncogene-induced senescence (OIS), which is a tumour suppressive mechanism important in melanoma, linking in this way OIS to the regulation of metabolism. Furthermore, we have identified the dependency on glutamine metabolism as an important adaptation occurring concomitantly with the acquisition of resistance to vemurafenib (BRAF inhibitor) in melanoma, which opens the possibility to combine therapies targeting glutamine metabolism with BRAF inhibitors, in order to overcome or avoid the onset of resistance in melanoma. Using the same strategy we have discovered an important mechanism of interregulation between glycolysis and amino acid metabolism, identifying the glucose-derived amino acid serine as an activator of the main isoform of pyruvate kinase present in cancer cells, PKM2. In addition, we provide new insights into the mechanism of allosteric regulation of this complex protein and a better understanding of the way it regulates central carbon metabolism. In summary, our results open new possibilities for the development of cancer therapies that manipulate metabolic adaptations found in cancer cells in order to kill them specifically or halt their growth.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: cancer, metabolism, metabolomics
Subjects: Q Science > Q Science (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences > Beatson Institute of Cancer Research
Funder's Name: UNSPECIFIED
Supervisor's Name: Gottlieb, Prof. Eyal
Date of Award: 2014
Depositing User: Miss Barbara Chaneton
Unique ID: glathesis:2014-5762
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 13 Nov 2014 12:01
Last Modified: 21 Aug 2017 14:49
URI: http://theses.gla.ac.uk/id/eprint/5762
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