Dual Epithelial and Stromal Targeting in Breast Cancer Using the Phase II ROCK2 Inhibitor KD025 Guided by Intravital Imaging Technology
Abstract
A key factor that limits the efficacy of drug treatment for breast cancer is extensive deposition of extracellular matrix (ECM) or fibrosis, which (i) hinders drug delivery and (ii) provides positive biomechanical feedback signaling to tumors to enhance tumor progression and treatment resistance. We have access to the clinically relevant ROCK2 inhibitor KD025 and have confirmed here that pharmacological ROCK2 inhibition can significantly reduce fibrosis in our breast cancer models. Using cell-derived matrix assays and collagen contraction assays, we have shown that ROCK2 inhibition significantly reduces ECM production and remodeling resulting in a softer ECM. Organotypic invasion assays showed that this inhibition of ECM remodeling (stromal targeting) in combination with ROCK2inhibition during breast cancer cell invasion (epithelial targeting) significantly reduces breast cancer cell invasiveness.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2023
- Accession Number
- AD1197737
Entities
People
- David Herrmann
- Paul Timpson
Organizations
- Garvan Institute of Medical Research