Targeting HIF-1 In Triple Negative Breast Cancer Using Glutaminase Inhibitors
Project Objective
It is now understood that Triple Negative breast cancer has many biologic nuances and a heterogeneity not previously understood. The aim of this project is to further characterise the role of HIF-1 in Triple Negative breast cancer and its response to inhibition and to assess its potential as a predictive biomarker of treatment response. 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 HIF-1 and its 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.
Outcome
This study investigated inhibition of glutaminase using CB-839 (a drug) to decrease HIF-1α levels by restoring PHD2 function. Two mechanisms were examined and while it was found decreased extracellular glutamate does decrease HIF-1α expression, the effect of decreasing (S)-2-HG abundance after CB-839 treatment appears to be predominantly responsible for the HIF-1α destabilising effects of glutaminase inhibition. While clear effects were observed in several TNBC cell lines grown in vitro, the process was not replicated in the in vitro effects observed.
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