Discovering Novel Therapeutics for Triple Negative Breast Cancer

Triple negative breast cancer (TNBC), associated with aggressive tumor behavior and worse outcomes, is the most challenging subtype in breast cancer. Chemotherapy remains the major treatment for TNBC, due to the lack of recognized molecular targets for therapy and the ineffectiveness of common treatments. Therefore, there is still an unmet need to discover novel TNBC therapies. A first-of-a-kind efficacy-based fingerprinting approach to identify potent anticancer candidates from natural products without the need for isolating individual components from the extracts is proposed. The fingerprint profiles of 22 ginger samples using liquid chromatography-mass spectroscopy were characterized and the anti-proliferative effects (IC50) of these samples on TNBC cells were evaluated. The supervised principal component analysis identified a subset of analytes whose abundance strongly associated with the IC50 values of the ginger extracts, providing a link between ginger extract composition and in vitro anticancer efficacy. Next, the effects of PIK75, a small molecule p110α and DNA-PK dual inhibitor, on TNBC treatment were evaluated. PIK75 showed potent inhibition effects in vitro on the growth, colony formation and cellular mobilization of TNBC cells, and decreased tumor growth in a mouse model. However, drug combination treatments on TNBC cells using single p110α and DNA-PK inhibitors did not show synergistic effects. Thus, there might be other pathways involved in the inhibition effects of PIK75 other than these two proteins. The discovery of novel lead compounds from natural products for TNBC based on NCI-60 human tumor cell lines screen data was investigated. Two series of compounds isolated or derived from Bridelia balansae Tutcher and Miliusa plants were tested for their anti-TNBC effects since they possess structural similarity with compounds recorded in NCI-60. Two miliusanes were chosen for anti-TNBC efficacy and mechanism study. The direct protein binding target of K1 was also identified. Overall, this dissertation demonstrated that alternative therapeutics can be found for treating TNBC. It focused on the discovery and development of TNBC novel therapeutics from both natural products and kinase inhibitors, which improved the drug discovery efficiency from natural products and could serve as pre-clinical profiles of the lead compounds