Translational metabolic treatments for breast cancer


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Adrian L Harris1
1University of Oxford, Oxford, UK

Abstract

Changes in metabolism are the essential output of many genetic lesions in cancer and these are required for tumour growth, invasion and metastasis. Many key mutations in breast cancer, particularly PIK3A, but also HER2 oestrogen receptor, are heavily involved. Hypoxia biology represents a key area of metabolic difference between tumour cells and normal cells and besides the aerobic glycolysis frequently induced by oncogenes, further metabolic changes are induced by hypoxia. We have investigated these in vitro and in vivo and found recently that upregulation of glycogen metabolism and lipid uptake is essential for survival under hypoxia. Blockade of glycogen breakdown or synthesis or inhibition of key fatty acid binding proteins contributes to a marked reduction of tumour growth in vivo. These results are with knockdown of enzymes or binding proteins that are targetable and suggest another way of selective toxicity to breast cancer. Their expressions also differ by intrinsic phenotypes for breast cancer, for example, the glycogen pathway seems particularly important for triple receptor negative breast cancer survival. Induced essentiality represents another way of exploiting the metabolic differences by using antiangiogenic drugs to increase hypoxia and make tumour cells far more dependent on specific metabolic pathways. These include carbonic anhydrase-9 to regulate acid pH, as well as the enzyme pyruvic dehydrogenase kinase to switch off mitochondrial metabolism. In addition, new pathways of hypoxia signalling in window of opportunity studies with bevacizumab and metformin we have shown marked induction of many of these pathways in patients with breast cancer under hypoxia and modulation of glucose metabolism by metformin. It will be of substantial interest to combine these therapies. However, it is likely that there will be great heterogeneity in response and trying to define patients, which show the optimum response to bevacizumab metabolically or to metformin will help appropriate stratification in prospective studies.