Evaluation of a Specific Cytotoxic Agent and Identification of a New Targetable Receptor for Human Triple-Negative Breast Cancer
Abstract
Despite significant advances in cancer research, breast cancer remains a serious global disease associated with high rates of mortality. Receptors for estrogen (ER), progesterone (PR), or HER2 have proven to be useful targets for therapeutic intervention of many types of breast cancer. However, breast tumors that lack these receptors, called triple-negative breast cancer (TNBC), have limited treatment options. A subtype of TNBC, called basal B TNBC, is extremely aggressive, and patients diagnosed with this subtype of breast cancer have an extremely poor prognosis. In fact, individuals suffering with basal B TNBC have an average post-diagnosis lifespan of only 2 years. Thus, it is critically important to identify new TNBC-specific receptors and novel therapeutic agents that bind these receptors to target this aggressive type of breast cancer. Genetic methods used to screen for uniquely expressed proteins have not identified specific cell surface proteins as therapeutic targets for TNBC. Other types of cell surface molecules, however, such as cell surface-exposed carbohydrates of gangliosides, likely differ between normal and cancer cells. Gangliosides are hybrid carbohydrate/lipid molecules expressed in many subtypes by different cells, which are important to cell signaling and, coincidentally, act as binding targets of naturally occurring bacterial enterotoxins. To test the hypothesis that ganglioside expression patterns vary between normal and breast cancer cells, we screened a variety of ganglioside-binding bacterial enterotoxins for activity against a panel of control and breast cancer cell lines. We found that LT-IIc, a member of the type II heat-labile enterotoxin subfamily, induces irreversible cell death specifically in mouse and human TNBC cell lines, an effect not observed when the cells are treated with LT-IIb, a toxin with binding affinity for different gangliosides. We hypothesize that gangliosides may represent a novel cell-surface target that can be employed to kill TNBC cells specifically, similar to the use of hormone and growth factor receptors as targets in other breast cancer subtypes. It is critical, therefore, to test whether the toxicity of LT-IIc for TNBC observed in vitro with use of TNBC cell lines also occurs in human TNBC tumors and is associated with specific ganglioside expression. The two aims of this grant proposal are to (i) determine the cytotoxic effects of LT-IIc on TNBC cells isolated from human tumors and (ii) identify the gangliosides expressed predominantly or unique expressed on TNBC cells that are bound by LT-IIc, but not by LT-IIb. These studies, while evaluating the potential of LT-IIc as a direct therapeutic agent, will also seek to identify gangliosides that are uniquely or predominantly expressed on TNBC cells as a new receptor on those cancer cells that can be exploited as a cell-surface target for intervention. This proposal addresses the Overarching Challenge, “Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival.” By developing a targeted therapy that affects only transformed TNBC cells, we hope to increase effectiveness, decrease toxicity to normal cells, and increase survival of women with the worst types of TNBC. Successfully completing this study on clinical specimens, rather than cell lines, is a critical step toward the novel development of ganglioside-targeting by enterotoxins and other pharmacological agents as a breast cancer therapy. The results of this study will enable us to develop a pilot clinical trial to evaluate the effects of LT-IIc in women suffering from TNBC. The high mortality and rapid progression associated with this type of breast cancer requires the rapid development of new, specific, safe, and effective treatment protocols, a goal that this project pursues.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810042
Entities
People
- Terry Connell
Organizations
- United States Army
- University at Buffalo