Investigating medulloblastoma metabolism for better diagnosis and treatment

Munford, Haydn (2019). Investigating medulloblastoma metabolism for better diagnosis and treatment. University of Birmingham. Ph.D.

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Abstract

Cancer cells are able to reprogram their metabolism in order to supply biosynthetic and bioenergetic demands of rapid proliferation. Glutamine is required by most cancers in significant quantities, as it serves as a major anabolic carbon and nitrogen source for synthesis of macromolecules, a source of high energy electrons for ATP production and the regulation of ROS homeostasis via glutamate through the synthesis of glutathione. The metabolism of glutamine in Medulloblastoma (MB) - the most common high grade childhood tumour – is largely unknown.

Using publically available databases of MB gene expression, we observed that genes associated with glutamine metabolism were prognostic in MB patients. Furthermore, employing a combination of analytical approaches to study metabolism, we show the importance of glutamine catabolism in MB cell lines. Finally, we investigated the effect of pharmacological manipulation of glutamine metabolism and observed that inhibition of glutaminase 1 (GLS1) – the enzyme responsible for glutamate biosynthesis - can increase cisplatin and irradiation cytotoxicity.

Taken together our data suggests that understanding glutamine metabolic pathways may generate prognostic bio-markers of survival and may serve to improve current therapies.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):