Accession Number:

AD1160522

Title:

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

Descriptive Note:

[Technical Report, Final Report]

Corporate Author:

UNIVERSITY HEALTH NETWORK TORONTO (ONTARIO)

Personal Author(s):

• Penn, Linda

Report Date:

2021-07-01

Pagination or Media Count:

122

Abstract:

We have shown that targeting the mevalonate pathway with fluvastatin preferentially 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 production of an important end-product of the mevalonate pathway essential for protein N-glycosylation associated with EMT. We have also shown that dipyridamoleDP potentiates fluvastatin-induced apoptosis of BrCa cells by blocking the statin-induced restorative feedback loop. We have also identified additional agents that can potentiate statin-induced BrCa cell death, thereby expanding this class of anti-cancer agents. We have published 3 manuscripts 2 at Cancer Research and Molecular Oncology, have another nearly ready for resubmission to Nature Communications, and have published a review article in Clinical Cancer Research. Thus, we have been highly productive and made advances that are actionable and have potential to immediately impact BrCa patient outcome.

Descriptors:

• health services
• medical personnel
• chemistry
• cell physiological processes
• antineoplastic agents
• oncology
• enzyme inhibitors
• statins
• cancer
• cells
• lymphocytes
• peptide growth factors
• breast cancer
• colon cancer
• gene expression
• stress (physiology)

Subject Categories:

• Medicine and Medical Research

Distribution Statement:

[A, Approved For Public Release]