Targeting Microtubule Associated Protein Tau in Ovarian Carcinoma to Increase Efficacy of Paclitaxel

摘要

ABSTRACT Mortality from epithelial ovarian carcinoma has not changed significantly over the past century. This disease still remains the deadliest gynecologic malignancy and the fifth leading cause of cancer death in women. The metastasis is the main cause of death from this morbid disease, and one of the key problems preventing successful treatment is chemotherapy resistance. The long-term goal of the studies in our laboratory is to characterize molecular mechanisms regulating ovarian carcinoma metastasis and its recurrent chemotherapy- resistant phenotype. The objective of the study outlined in this proposal is to determine the efficacy of targeting the microtubule-associated protein tau to increase paclitaxel response. Patients with advanced ovarian carcinoma are typically treated with surgery and a combination chemotherapy containing a taxane (most commonly, paclitaxel) and a platinum agent. Furthermore, paclitaxel is used as a second line agent in relapsed platinum-refractory epithelial ovarian cancer. Previous studies have linked several different molecular mechanisms with paclitaxel resistance; however, so far, there are no clinically used strategies to overcome these mechanisms. More recent previous studies, including those from our lab, have linked expression of tau with resistance to paclitaxel in specimens of serous ovarian carcinoma. Our data suggest that the number of tau-positive cases in the metastasis significantly increases compared to primary cancer. We have also demonstrated that downregulation of tau expression in cell culture models synergistically sensitized cells to paclitaxel. This suggests that strategies to reduce tau levels or its expression could benefit outcomes of the paclitaxel treatment in metastatic ovarian carcinoma. Importantly, as aberrant tau has been also associated with a number of neurodegenerative diseases significant efforts in this field has been made to develop inhibitors and drugs targeting tau to treat these debilitating conditions. However, it remains to be established whether tau-based drugs and inhibitors could be used to increase paclitaxel sensitivity in ovarian carcinoma. We are partnering with a neuroscientist, Dr. Peter Penzes (Northwestern University) to determine the efficacy of tau inhibitors in preclinical models of ovarian cancer. In this application we hypothesize that drugs targeting tau, which were originally developed to treat neurodegenerative diseases, will synergize with paclitaxel in increasing its cytotoxicity and reducing clone formation of HGSOC cells, resulting in significantly reduced tumor burden in vivo. To test this hypothesis, we propose these specific aims: 1) to validate the efficacy of the combination of tau-based therapeutics and paclitaxel in pre-clinical models of HGSOC, and 2) to validate tau-based therapeutics in their efficacy to re- sensitize paclitaxel-resistant ovarian carcinoma to the paclitaxel treatment. The proposed experiments will be conducted using preclinical models of high grade serous ovarian carcinoma, including cell culture and xenograft models.