Targeting the Mevalonate Pathway and its Restorative Feedback Loop in Breast Cancer
Abstract
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 dipyridamole(DP) potentiates fluvastatin-induced apoptosis of BrCa cells by blocking the statin-induced restorative feedback loop. Unexpectedly, evaluation of the fluvastatin+DP 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 fluvastatin+DP 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2019
- Accession Number
- AD1094879
Entities
People
- David Cescon
- Linda Z Penn
Organizations
- University Health Network