Targeting the Mevalonate Pathway and its Restorative Feedback Loop in Breast Cancer
Technical Report,01 Apr 2018,31 Mar 2019
University Health Network Toronto Canada
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During this past year of DOD funding, we have shown that targeting the mevalonate pathway with fluvastatin specifically induces apoptosis in breast cancer BrCa cells that have undergone epithelial-to-mesenchyme transition EMT, a critical process for the initiation of metastasis. Moreover, we have identified that EMT gene expression is bimodally distributed and is a biomarker of fluvastatin sensitivity. Mechanistically, we have shown that fluvastatin can induce apoptosis by limiting geranylgeranyl-pyrophosphate GGPP and dolichol, an important end-product of the mevalonate pathway essential for protein N-glycosylation. We have also shown that dipyridamoleDP potentiates fluvastatin-induced apoptosis of BrCa cells by blocking the statin-induced restorative feedback loop. Unexpectedly, evaluation of the fluvastatinDP combination was not possible in mouse models of BrCa due to toxicities associated with long-term administration of DP in mice. Importantly, this is not an issue when fluvastatinDP are co-prescribed in humans. We have also identified additional agents that can potentiate statin-induced BrCa cell death, thereby expanding this class of anti-cancer agents.
- Medicine and Medical Research