A233: Targeting the glycolytic and inflammatory phenotype in breast cancer
1University of Manchester, Manchester, UK
Increased glucose metabolism, or glycolysis, is a prominent feature of malignant tumours. Enhanced glycolysis can be caused by genetic alterations in tumour cells and in response to hypoxia, mediated via induction of hypoxia-inducible factor-1 (HIF-1), leading to changes in the expression patterns and activity of glycolytic enzymes. Hypoxia is associated with more aggressive tumour types and it has been previously proposed that altered metabolism may contribute to this phenotype. Targeting the glycolytic phenotype of cancer cells in both normoxic and hypoxic conditions may yield significant benefit in treating aggressive tumour types.
The metastatic MDA231 breast cell line (highly glycolytic in normoxia, high levels of HIF-1?) was compared with the non-metastatic MCF-7 breast cancer cell line (low HIF-1? expression and glycolysis in normoxia). Cell cultures and xenografts (MDA231) were subjected to treatment with a putative modulator of glycolytic activity: XMD8-92 under both normoxic and hypoxic conditions. Responsiveness to therapy was assayed using tumour volume measurements, lung clonogenics and DCE and ADC-MRI in vivo and by glucose consumption (Seahorse), gene expression analysis and survival assays in vitro.
Our results demonstrate the XMD8-92 affects MDA231 and MCF7 cells in both normoxic and hypoxic conditions. However, whilst the drug induces cell death in normoxic conditions in both cell lines, it appears to confer a selective survival advantage to MDA231 cells under hypoxic conditions. This correlated with both differing expression levels of hypoxia-inducible gene products (glut-1 and vegf) and glycolytic signatures (glycolytic capacity, glycolytic reserve and non-glycolytic acidification), between the two cell lines, post-treatment. Additionally, we found that XMD8-92 treatment decreased pro-tumourigenic inflammatory signalling in both cell lines. Interestingly, in vivo XMD8-92 therapy translates to a decrease in both primary MDA231 tumour burden and metastatic spread.
XMD8-92 has the potential to be an effective therapy for breast cancer in both treatment of the primary tumour and the prevention of metastatic spread.