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Targeting HIF-1 in triple negative breast cancer using glutaminase inhibitors

37 months
Approved budget:
Dr Dean Singleton
Health issue:
Cancer (oncology)
Proposal type:
Breast Cancer Research Project
Lay summary
Low-oxygen (hypoxia) is a common feature of breast tumours that promotes aggressive disease outcomes and poor patient survival. Hypoxia is “sensed” in cells by a protein called hypoxia-inducible factor 1 (HIF-1). HIF-1 accumulation in oxygen-deprived cancer cells promotes the growth of new tumour blood vessels and causes cancer cells to become invasive and resistant to anticancer therapy. Interestingly, certain triple negative breast cancers (TNBC) make and secrete the amino acid glutamate. Glutamate accumulation in the tumour interferes with uptake of cysteine and this causes activation of HIF-1, even when oxygen is abundant. Using drugs to block glutamate production (glutaminase inhibitors), we demonstrated reduced glutamate secretion and increased degradation of HIF-1. Glutaminase inhibitors are showing clinical activity in studies of heavily treated, therapy-resistant TNBC. Our work aims to further characterise the role of HIF-1 in TNBC response to glutaminase inhibition and assess its potential as a predictive biomarker of treatment response.