Metastasis is a key factor for poor prognosis in cancer patients. Breast cancer is the most common invasive cancer in women and the second-most common cause of death in American women. Triple negative breast cancer tends to be both unresponsive to chemotherapy and more aggressive than other types of breast cancer. New therapies to prevent its spread are sorely needed. The goal of this work is to optimize our newly discovered series of novel and selective antagonists of the LPA1 receptor (LPA1R) as agents to prevent metastasis in triple negative breast cancer. Preliminary work indicates that LPA1R antagonism results in a profound inhibition of the migration of triple negative breast cancer cells. In this work, new compounds will be identified utilizing our assay cascade combining in vitro receptor pharmacology and cell mobility assays to select lead molecules. Candidate ligands will be designed and synthesized using a series of recognized approaches in medicinal chemistry. This work will confirm the involvement of LPA1R in the migration of triple negative breast cells and determine the utility of LPA1R antagonists as potential agents for adjunctive chemotherapy of a devastating illness. Our study will open up a new avenue of target-specific drug development for specific types of breast cancer patients such as TNBC.
Triple negative breast cancer (TNBC) is a type of breast cancer that is negative for the estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor 2 (Her2). Since hormonal therapy does not work for TNBC, other anti-tumor agents (such as cisplatin) have been attempted, but with little success. Lysophosphatidic acid (LPA) is an endogenously produced bioactive phospholipid which has growth factor-like activity and pro-migration properties. In this proposal, we will develop novel small molecule LPA1R antagonists and evaluate them as novel anti- cancer drug candidate for human TNBC patient treatment.