Epithelial ovarian cancer is a rapidly progressive, highly lethal disease, usually diagnosed at late stage. Surgical debulking followed by platinum and taxane based chemotherapy has been the standard of care for the past two decades; there are no approved targeted therapies for ovarian cancer. With standard therapy, the vast majority of ovarian cancer patients develop recurrent disease and resistance to chemotherapy. Resistance to chemotherapy has been attributed to a limited population cancer cells with stem cell like properties. We recently demonstrated that chemotherapy resistant ovarian cancer stem-like cells (CSC) can be identified by a protein activity known as ALDH. The unique expression of this protein/s in CSC allows a unique opportunity to develop therapeutics specifically targeting CSC.
We have developed novel ALDH inhibitors which appear to induce ovarian CSC cell death. CSC appear to die by a novel mechanism, completely different from platinum/taxane induced cell death. We propose to identify and characterize the mechanism whereby ALDH inhibition. We hypothesize that, given the unique mechanism of cell death, ALDH inhibitors will synergize with chemotherapy and assess whether elimination of ovarian CSC by ALDH inhibition will sensitize bulk tumor cells to platinum/taxane based chemotherapy. Taken together, these studies will expand our understanding of the function of ALDH in ovarian CSC and provide critical pre-clinical studies for a potential novel CSC targeted therapeutic to prevent recurrent disease.