Targeting Tumour Metabolism for Cancer Therapy and Diagnosis


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2015-2021

FUNDING AMOUNT

N/A

ABSTRACT

Background: The growth and proliferation of cancer cells is fundamentally dependent on metabolic processes, and altered cell metabolism is regarded as a hallmark of cancer. To sustain enhanced growth, cancer cells become highly dependent on the uptake of exogenous nutrients, particularly amino acids. Additionally, by-products of up-regulated metabolic pathways must be released to maintain favourable metabolite concentration gradients and avoid toxicity. Inhibiting transporters that account for cancer-associated nutrient uptake and release is an attractive new anti-cancer drug development strategy. Furthermore, altered tumour metabolism causes systemic metabolic alterations (detectable in biological samples such as blood and urine) that can be used to improve cancer diagnosis and clinical decision-making. Aims: I will exploit cancer-specific nutrient uptake and release to identify new ways to treat and diagnose cancer. To achieve this goal I will target amino acid metabolism; my work has shown that in pre-clinical models of cancer, dietary limitation of serine suppresses tumour growth. I will investigate the mechanisms of cancer-specific serine uptake and begin development of new compounds to inhibit this process. In addition, I have found that pancreatic ductal adenocarcinoma (PDAC) models are unresponsive to serine limitation, likely due to the ability PDAC cells to derive amino acids from whole proteins. I aim to investigate and exploit this metabolic characteristic of PDAC, and develop new therapeutic and diagnostic strategies for this deadly form of cancer. Aim_1. Target cancer-specific amino acid metabolism: a. Elucidate the nutrient transporters responsible for serine uptake and glycine release in cancer cells and initiate development of small molecule inhibitors b. Define PDAC-specific AA metabolism to identify therapeutic targets Aim_2. Utilise metabolomics to establish new diagnostic & treatment stratification strategies for PDAC a. Use biological samples from patients to define metabolic signatures that can be used to diagnose PDAC b. Assess the utility of metabolomics for use in PDAC treatment stratification Methods: The critical technique for these studies will be liquid chromatography mass spectrometry metabolomic analysis, performed in unbiased and targeted (e.g. using 13C tracer flux) analyses, performed on human biological (patient) samples, cell culture, and mouse models. A range of molecular biology techniques for analysis / manipulation of DNA, RNA & protein will complement metabolomics. Results will be used to: -Improve our understanding of the basic biology of cancer -Identify new therapeutic targets in PDAC -Provide candidate nutrient transport inhibitors for drug development -Diagnose PDAC earlier -Improve PDAC treatment stratification More... »

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