Targeting the Novel TXNRD1-cGAS-SASP Axis to Eradicate Stemlike Cells in Epithelial Ovarian Cancer
Abstract
Areas of Emphasis Relevance: (1) Understand the basic biology of ovarian cancer progression and recurrence and (2) Develop novel therapeutic strategies for treatment and prevention. Rationale and Objective: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer in the United States with only 30% of patients living for 5 years or more. The standard of care for EOC is platinum-based therapy. Although the majority of EOC patients respond to chemotherapy well initially, relapse ultimately occurs with resistance. Emerging evidence suggests that cancer stem-like cells (CSCs) contribute to chemotherapy resistance. However, approaches to eliminate CSCs in EOC remain an unmet need. Platinum-based therapy is known to induce senescence in EOC. Senescence is tumor suppressive by halting the proliferation of cancer cells while secreting a number of proinflammatory and pro-growth factors known as the senescence-associated secretory phenotype (SASP). Increasing evidence support that senescent cells contribute to chemoresistance by inducing CSCs through the SASP. However, directly eliminating senescent cells is not ideal because senescent cells are important to normal tissue structure and function. Therefore, it would be an ideal strategy to overcome chemoresistance by selectively eliminating the detrimental SASP while maintaining the tumor-suppressive role of senescence-associated growth arrest. In the proposed studies, we will explore this possibility by focusing on a newly discovered pathway that centers on a protein called TXNRD1. Of note, small molecule inhibitors of TXNRD1 that can be applied to this approach are already available. Our proposal consists of two aims. First, we will investigate the mechanism underlying the SASP regulation by TXNRD1 during platinum-induced senescence. Second, we will develop a novel approach to overcome platinum-induced resistance by eliminating stem-like cells through targeting TXNRD1. Taken together, the objective of the proposed studies is to develop a novel therapeutic strategy to eradicate the CSCs induced by platinum-based chemotherapy in EOC by inhibiting TXNRD1. Impact and Ultimate Applicability: We anticipate that this work could benefit ovarian cancer patients by developing urgently needed strategies for therapy-induced relapse. The ideal outcome would be that a combination of platinum and inhibitors targeting the TXNRD1 could be utilized to eliminate the CSCs to overcome chemoresistance in EOC. In the immediate short term, the proposed studies will provide fundamental mechanistic insights into the role of TXNRD1 in regulating platinum-associated therapy relapse in EOCs. This sets the stage to ultimately develop an effective approach to target this newly discovered pathway. In the long term, the completion of the proposed studies will provide a scientific rationale for developing novel therapeutic strategies for chemoresistance and relapse in EOC, which is essentially incurable at the moment. If successful, this research will have a transformative impact on the management of chemoresistant EOC, a major clinical challenge.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310729
Entities
People
- Hao Xue
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army