Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Development of gene expression profiles for murine breast tumours treated with Sunitinib

ABSTRACT: In order to establish a profile of gene expression of tumours treated with sunitinib, 4T1 breast tumours were allowed to establish in Balb/C mice for 1 week. The mice were then treated with 40 mg/kg Sunitinib in PBS and 3.72% DMSO (treatemt group) or PBS-DMSO vehicle alone (no treatment group), daily for the period of the experiment, after which the tumours were resected homogenised and subjected to CD31 microbead separation of endothelial cells and bulk tissue, both of which were subjected to agilent microarray analysis. Treated tumours greater than 250 mm3 (by caliper measurement) after 8 days of treatment were considered resistant to treatment, those smaller than this were considered sensitive to sunitinib treatment. Total RNA was extracted from each tumour sample using the Qiagen miRNAeasy kit, processed into cRNA using the Agilient low input, one colour labelling kit, hybridised onto the 8 x 66k whole mouse genome expression microarrays. Data was normalised in R64 and comparison matrices between treated and untreated endothelum and bulk fractions were constructed. Genes whose expression was significantly altered by sunitinib treatement were taken forward for further analysis.

ORGANISM(S): Mus musculus

SUBMITTER: Joseph Wragg

PROVIDER: E-GEOD-84048 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background Sunitinib is a small molecule tyrosine kinase inhibitor approved for the treatment of diverse cancers. Despite widespread clinical approval the associated cardiovascular toxicity sequelae are of concern; high grade toxicities may lead to dose reduction, interruption or discontinuation. Thus, an effective strategy for the early detection of cardiac damage in the context of sunitinib treatment is warranted. Although yet to be fully elucidated, molecular pathways and kinases implicate include those related to cardiac energy metabolism. We hypothesised that plasticity in cardiac metabolism could represent a novel early marker of cardiotoxicity. Methods and Results Female Balb/CJ mice (n = 36) or Sprague-Dawley rat (n = 12) models were treated with sunitinib. Physiological parameters were measured. An hypothesis driven cardiac positron emission tomography (PET) approach was implemented to investigate alterations in myocardial glucose, fatty acid and oxidative metabolism. Following treatment, blood pressure increased, whilst left ventricular ejection fraction decreased in both models. Increased myocardial glucose uptake after 48 hours indicated early perturbations in glucose metabolism. Myocardial fatty acid metabolism appeared increased as a result of sunitinib treatment indicated by PET but electron microscopy revealed significantly increased storage of lipids in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top cardiac signalling pathways perturbed by sunitinib treatment. [11C]Acetate-PET data suggested a decrease in myocardial perfusion following 5 days of treatment. Conclusions Data implicates sunitinib as a mediator of compromised myocardial energy metabolism. Increased reliance on glycolysis, increases in myocardial lipid deposition and perturbed mitochondrial function may ultimately result in a fundamental energy crisis manifesting as compromised cardiac function, the long term effects of which are unknown. Our data support the utility of an hypothesis driven PET approach to monitor cardiac metabolic pathway remodelling in response to sunitinib, which may ultimately have clinical utility as a novel safety imaging biomarker strategy.

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Development of gene expression profiles for murine breast tumours treated with Sunitinib

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