Accession Number:

AD1094879

Title:

Targeting the Mevalonate Pathway and its Restorative Feedback Loop in Breast Cancer

Descriptive Note:

Technical Report,01 Apr 2018,31 Mar 2019

Corporate Author:

University Health Network Ontario Canada

Personal Author(s):

Report Date:

2019-04-01

Pagination or Media Count:

103.0

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 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.

Subject Categories:

  • Medicine and Medical Research
  • Anatomy and Physiology
  • Pharmacology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE