Targeting DCLK1-Driven Chemoresistance in Ovarian Cancer
Abstract
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy and is characterized by repetitive disease recurrences due to the development or persistence of chemotherapy and targeted therapy-resistant tumors. There is an urgent need to develop new therapeutic strategies that target key pathways in the evolution of chemoresistance and drive HGSOC recurrence. It is hypothesized that drug-resistant features associated with HGSOC recurrence patterns occur due to the evolution and enrichment of cancer stem cell (CSC)-like cells in recurrent/persistent tumors. CSCs retain the ability to self-renew and activate plasticity pathways to propagate new tumors and are especially resistant to chemotherapy. The CSC-related protein, doublecortin-like kinase 1 (DCLK1), is overexpressed in various solid tumors, including high-grade epithelial ovarian cancer, and is a major regulator of stemness programs, epithelial-to-mesenchymal transition - which drives tumor invasion and metastasis, drug resistance, and tumor cell dormancy in this highly lethal neoplasm. Our preliminary data implicate DCLK1 in the regulation of acquired resistance to platinum-based therapy in HGSOC and indicate that inhibition of DCLK1 enhances sensitivity to platinum-based chemotherapy by working in synergy to kill resistance cells. We hypothesize that DCLK1 drives cisplatin resistance in HGSOC by promoting cancer-cell stemness programs and that targeting DCLK1 in combination with platinum-based chemotherapy will combat resistance in HGSOC. This proposal directly addresses two of the Ovarian Cancer Research Program’s Areas of Emphasis: 1. Understand the basic biology and etiology of ovarian cancer initiation, progression, metastasis, recurrence, genetics, and other critical events. 2. Develop novel therapeutic strategies for treatment and prevention. At the completion of this study, we will have evaluated the mechanism by which DCLK1 drives resistance to platinum-based chemotherapy, optimized the various therapeutic strategies to target DCLK1, and determined the efficacy and mechanism of targeting DCLK1 to overcome resistance in preclinical models. We expect that this research will reveal new treatment strategies that can be evaluated in the near term to improve overall outcomes for ovarian cancer patients. Specifically, therapeutic targeting of DCLK1 could be used clinically in combination with front-line chemotherapy to enhance tumor cell killing at initial treatment and may also be used as a maintenance therapy by specifically targeting CSC-like cells to prevent recurrences. The long-term outcomes of this study are the identification of a new therapeutic target that can be applied directly to the clinic to improve therapeutic outcomes and extend life in patients with OC. Improving therapeutic outcomes and extending life for ovarian cancer patients will directly impact the health and well-being of Service Members, Veterans, their Families, and all women impacted by this highly lethal disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310223
Entities
People
- Bethany Hannafon
Organizations
- United States Army
- University of Oklahoma Health Sciences Center