Targeting Discoidin Domain Receptors in Prostate Cancer
Abstract
We report the results of our studies focusing on the Discoidin Domain Receptors (DDRs), a set of kinase receptors that signaling response to collagen. The projects goals were to define the expression and therapeutic potential of DDRs in prostate cancer. We conducted a comprehensive analyses of DDR1 expression in a 200 case Grade/Stage tissue microarray (TMA) with clinical data, using a highly specificanti-DDR1 antibody. DDR1 positive staining was found in the membrane, cytoplasm and nucleus of benign and tumor cells. Comparing low [less than 7(3+4)] and high [greater than 7(3+4)] Gleason Score (GS) tumors, we found that PCa malignant progression is associated with reduced expression of DDR1 in the plasma membrane of tumor cells of high GS tumors. Thus, there is a loss of membranous DDR1 in aggressive PCa. We also found that DDR1 membranous expression in cancerous tissue is an independent predictor for tumor aggressiveness with statistically significant Odds Ratio (p = 0.001). In vitro cellular fractionation studies demonstrated that DDR1 distributes between membrane, cytoplasm and nuclear fraction, even after collagen stimulation. A selective anti-human DDR1 neutralizing antibody was used to examine its effect on intraosseous tumor growth. We found a tendency towards reduced tumor burden when PC3M-Luc2 cells were pre-treated with the blocking antibody before intratibial inoculation. However, treatment had no impact on established intraosseous tumors. However, target inhibition could not be determined. Overall, our studies helped to define the association between DDR1 and PCa progression and the challenges of targeting active DDR1 in the bone microenvironment when using tumor xenografts.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2021
- Accession Number
- AD1149937
Entities
People
- Rafael Fridman
Organizations
- Wayne State University