Researchers at the MUSC Hollings Cancer Center have created a new compound that shows promise in addressing chemotherapy resistance in triple-negative breast cancer. This compound could also have applications in treating fibrotic conditions such as liver fibrosis or pulmonary fibrosis.
The key focus of this research is to prevent the protein lysyl oxidase (LOX) from excessively stiffening the environment around tumors, a process known as desmoplasia, which can hinder the effectiveness of chemotherapy.
Ozgur Sahin, Ph.D., the SmartState Endowed Chair in Lipidomics and Drug Discovery, explained, “The primary role of LOX is to create stiffness in the tumor microenvironment by crosslinking collagens and elastins in the extracellular matrix. This stiffness acts as a barrier that limits drug penetration, including chemotherapy.”
By utilizing a LOX inhibitor, researchers aim to soften this structure, allowing drugs to penetrate more effectively.
The Sahin Lab, in collaboration with researchers from Hollings and the University of South Carolina College of Pharmacy, recently published a paper in Cell Chemical Biology introducing this innovative compound.
Previous work by Sahin demonstrated the significant role of LOX in chemotherapy resistance, leading to the development of this new compound.
Collaborating with Campbell McInnes, Ph.D., and Peggi Angel, Ph.D., the team conducted advanced tests beyond measuring LOX activity in tissues, including using MALDI-MSI to analyze the impact of their inhibitor on collagen architecture and other structural proteins.
Through altering the extracellular matrix architecture for enhanced drug penetration, the LOX inhibitor facilitates chemotherapy-induced production of reactive oxygen species (ROS) that can cause DNA damage and cell death. Additionally, inhibiting LOX blocks focal adhesion kinase (FAK) signaling, which would otherwise aid in DNA repair, thereby overcoming chemotherapy resistance.
This breakthrough was observed in various models, including triple-negative breast cancer cell lines, in vivo models, and organoid models derived from patient tumors.
Sahin’s research primarily focuses on triple-negative breast cancer due to its limited treatment options, but the LOX inhibitor could also potentially benefit patients with pancreatic or kidney cancer, which are also characterized by stiffness.
The current lead compound shows stability and no signs of toxicity, but the team plans to refine it further over the next few years to prepare for an Investigational New Drug (IND) application with the FDA, paving the way for clinical trials.
Sahin emphasized, “Drug development is an ongoing process. While our current compound is promising, we are continuously optimizing it. By partnering with USC, we are developing new versions of this molecule and testing them in various biological and pharmacological assays.”
