Targeting Precursor Neural (N)-Cadherin to Eliminate Chemotherapy-Resistant Triple-Negative Breast Tumor Cells
Abstract
Breast cancers can be divided into multiple subtypes. Some of these subtypes (e.g., estrogen-receptor+) can be treated successfully with targeted therapies and are thus associated with a good patient prognosis. In contrast, targeted therapies are not available for triple-negative (TN) breast cancers, a subtype diagnosed frequently in women under age 45 and in African Americans. Although many women with TN breast cancer show a partial response to chemotherapy, some cancer cells survive treatment. These residual tumor cells result in tumor recurrence and patient mortality within 5 years of diagnosis. To improve patient survival, there exists an urgent need to identify therapeutic targets in chemotherapy-resistant TN tumor cells. While chemotherapy effectively kills the bulk of TN breast tumor cells, a subpopulation of tumor cells, representing only a fraction of the total tumor, survive chemotherapy treatment, and are responsible for tumor recurrence. Our laboratory has established a novel method for enriching for tumor cells that survive chemotherapy, allowing us to identify novel resistance determinants. Founded on promising preliminary results, this proposal addresses the feasibility of targeting a novel tumor-specific protein to eliminate chemoresistant TN breast tumor cells. Our preliminary results demonstrate that chemoresistant TN tumor cells express a protein (precursor neural (N)-cadherin) on their cell surface that is not expressed on the surface of normal adult human cells. Importantly, we also showed that cell surface precursor N-cadherin is expressed on primary tumor cells from TNBC patients. Based on these findings, our laboratory arranged a collaboration with a cell biologist (Dr. Wahl) studying precursor N-cadherin functions in neurons. Dr. Wahl kindly provided our laboratory with an antibody that binds to precursor N-cadherin. Preliminary results show that this antibody binds to precursor N-cadherin on the surface of chemoresistant TN tumor cells, resulting in their death. Importantly, this antibody does not bind to neurons or other adult cells because precursor N-cadherin is not expressed on their cell surface. These findings are exciting because they suggest that this antibody can eliminate chemoresistant TN breast tumor cells without affecting normal cell viability, making it an attractive candidate as a TN breast cancer therapy. The current proposal addresses the efficacy of a novel combination therapy (chemotherapy + precursor N-cadherin antibody) for TN breast cancer in vitro and in an animal model. Our proposed studies are innovative in investigating the ability of an antibody to eliminate chemoresistant TN breast tumor cells without influencing viability of cells in normal human tissues. We have included on our team a long-term clinical collaborator (Kelly Marcom, M.D.), who is highly experienced in conducting clinical trials. Dr. Marcom will insure that promising results from these studies lead to near-term clinical trials testing the (1) safety of administering a humanized form of this antibody to patients and (2) ability of this antibody, when administered to TNBC patients following chemotherapy treatment, to prevent future tumor recurrence. Our studies have the potential to transform our treatment strategy for TN breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710046
Entities
People
- Robin E. Bachelder
Organizations
- Duke University
- United States Army