Tumor relapse and acquired chemotherapy resistance are two major factors leading to the high mortality of epithelial ovarian cancer (EOC) patients. It has become increasingly evident that ovarian cancers contain subpopulations of cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance. These CSCs are believed to be responsible for treatment failure and tumor relapse. However, it is still unclear how CSCs survive DNA-damaging agent treatment, and how the tumor regenerated by the surviving CSCs develops chemoresistance. Error-prone translesion DNA synthesis (TLS), a DNA damage tolerance mechanism that bypasses DNA damage during replication, has been suggested to mediate acquired chemoresistance. Our recent studies have revealed that ovarian CSCs show elevated expression of TLS polymerase ? (Pol?); we also demonstrated that Pol? is critical to the survival of ovarian CSCs following cisplatin treatment. Based on this scientific premise, we generate a hypothesis that enhanced Pol?-mediated TLS in CSCs contributes to tumor relapse and the development of acquired cisplatin-resistance after initial cisplatin treatment, by facilitating CSC survival and increasing CSC mutagenesis. The main objective of this proposal is to determine a novel mechanism that contributes to EOC relapse and chemotherapeutic resistance following initial cisplatin treatment.
Two specific aims are proposed to test this hypothesis and achieve our goal.
In specific aim 1, we will determine the contribution of Pol?-mediated TLS to EOC relapse after cisplatin treatment.
In specific aim 2, we will delineate the contribution of Pol?-mediated TLS to the development of acquired cisplatin resistance in the EOC and cisplatin-induced mutations in ovarian CSCs. The rationale under this proposal is that understanding the mechanism underlying tumor relapse and chemotherapy resistance would facilitate the development of new therapy strategies to improve the outcome of patients with EOC. It is our expectation that at the conclusion of this project, we will have provided solid evidence showing that enhanced expression of Pol? in ovarian CSCs contributes to the tumor regrowth, mutagenesis in CSCs, and the development of cisplatin resistance after initial cisplatin treatment. Downregulation of Pol? would significantly inhibit tumor relapse and prevent the development of cisplatin resistance, and thus, can be exploited for a new therapy strategy for EOCs.
Ovarian cancer is the fifth leading cause of cancer-related deaths in women in the United States. Most of the tumors are initially responsive to platinum-based chemotherapy, and the majority of signs and symptoms of cancer are gone. However, cancer can come back and become resistant to the drug. Indeed, 90% of the deaths from ovarian cancer are due to tumor return and drug resistance. Poor understanding of this drug resistance is a critical cancer research challenge. In this project, we plan to determine the role of cancer stem cells and their genomic instability in the tumor recurrence and the subsequent development of cisplatin resistance. Ultimately, we hope to identify new ways to increase the longevity of cancer patients.
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