Exploiting metabolic vulnerabilities induced by dietary restriction as novel therapies for infant leukaemia

Professor Christina Halsey and Professor Katrin Ottersbach

Infant leukaemia is an aggressive malignancy with cure rates of less than 50%. Importantly, despite large international trials, there has been no improvement in survival over the last 2 decades. The major challenge is that while infant leukaemia is aggressive, necessitating high-intensity treatment strategies, babies are extremely vulnerable to toxicity from chemotherapy and stem cell transplantation. Novel non-toxic therapeutic approaches are desperately needed.

In this project you will follow-up on exciting observations that manipulating dietary intake of key nutrients, such as the amino-acid serine, sensitises leukaemia cells to drugs targeting key metabolic pathways such as nucleotide synthesis, lipid biosynthesis and cellular responses to energetic stress. One stumbling block in developing dietary interventions for cancer treatment to date has been the unpalatability of many nutrient restricted diets. However, Infant ALL is particularly suited to thisapproach because babies are usually fed via nasogastric tube or intravenously during chemotherapy, making dietary interventions easy to control and deliver.

The key research question is “Does dietary restriction of serine induce novel metabolic vulnerabilities in infant leukaemia and can this identify new less-toxic and more effective therapies”. To answer this question you will first grow infant leukaemia cell lines in vitro and investigate the effects of serine starvation on serine synthesis, cellular growth, survival, gene expression, oxidative stress and energy production. You will then take a hypothesis-driven approach by combining serine starvation with inhibition of the key compensatory pathways activated in the presence of serine starvation. This will be complemented by novel discovery science using a 2893-compound high-throughput metabolism targeting library – available in our laboratory – which will identify novel drug targets in an unbiased fashion.

Following ranking of the most promising drug targets and confirmation of mechanisms of action in vitro, you will then be able to investigate the effects of the new therapy in vivo. The Ottersbach laboratory has developed a mouse model that recapitulates the clinical and biological features of infant leukaemia (ref 2). Using this model the effect of the drug on leukaemia growth will be compared between mice fed a normal diet and a serine-depleted diet. At the end of the experiment leukaemia cells will be harvested and analysed ex vivo to compare effects seen in vitro with the more complex in vivo environment. In this way you will identify promising new diet/drug combinations suitable for moving towards clinical use.

This project will provide you with training and experience in a wide variety of experimental techniques in the fields of cancer metabolism, therapeutic target identification and animal modelling. The CRUK Scotland Cancer Centre has a world-class reputation in these areas, and you will have access to all the necessary support and facilities to undertake this exciting PhD.

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