Role and Regulation of ZNF217 in Ovarian Cancer Metastasis and Drug Resistance
Abstract
Ovarian cancer continues to be the most lethal gynecologic cancer and the fifth leading cause for cancer-associated deaths among women in the United States. Due to the absence of obvious symptoms and the lack of reliable methods to identify ovarian cancer early, the majority of women are diagnosed at an advanced stage. At this stage, the cancer is no longer confined to the ovary and unfortunately, the existing drugs are ineffective. This limitation of extant drugs and therapeutic strategies is a major reason for the high mortality rate associated with ovarian cancer. This clinical reality highlights the urgent need to develop new and more effective ways to treat this deadly disease and translate them rapidly to the clinic. My long-term goal is to develop treatment strategies for advanced stage metastatic ovarian cancer and eliminate ovarian cancer associated deaths in women. Thus, through my research, I aim to benefit Service Members, Veterans, retirees, their Family members, and all women impacted by this deadly disease. In this proposal, I outline my plan to achieve this goal by characterizing a novel therapeutic target in ovarian cancer cells and determining its utility in addressing the deficiencies in extant treatment options. We discovered that a protein called Zinc Finger Protein 217 (or ZNF217) has great utility as a therapeutic target in metastatic ovarian tumors. ZNF217 is overexpressed in ~60% metastatic ovarian tumors and is associated with poor prognosis. Our data shows that ZNF217 promotes proliferation, metastasis, and drug resistance in ovarian tumors. However, the ZNF217’s utility as a therapeutic target in ovarian cancer has remained unexploited. We hypothesize that ZNF217 depletion will impair tumor progression and sensitize drug-resistant ovarian tumors to clinically approved chemotherapeutics. As drug resistance is the major challenge that limits the effectiveness of extant drugs, we believe our studies will address a critical need in ovarian cancer therapeutic development. In addition to promoting chemotherapeutic resistance, we discovered a link between ZNF217 and another key ovarian cancer risk factor, estrogen. Ovarian cancer cells that overexpress ZNF217 exhibited increased metastatic potential in the presence of estrogen. While estrogen is known to impact ovarian cancer incidence and progression, drugs that target estrogen signaling pathway have not been successful as a therapeutic strategy for ovarian cancer so far. We believe the limited effectiveness of FDA approved estrogen targeting drugs to be largely due to our inability to distinguish estrogen responsive ovarian tumors from non-responsive ones. Biomarkers that will allow us to make this important distinction will enable us to identify patients who would benefit from estrogen targeting therapeutics. Based on our exciting data, we hypothesize that ZNF217 levels in ovarian tumors has utility to serve as a predictive biomarker for identifying estrogen-responsive ovarian tumors. We will test this hypothesis using clinically relevant models of metastatic ovarian cancer. Interestingly, we found that ZNF217 also regulates several factors that are known to induce exclusion of immune cells from ovarian tumors. Such immune cell deficient tumors are highly prevalent in ovarian cancer and are associated with poor prognosis. The lack of immune cells in these tumors are also believed to be the major reason for the ineffectiveness of immunotherapy in ovarian cancer. To improve immunotherapy’s efficacy in ovarian cancer, we must convert these immune cell deficient tumors into one that is infiltrated with immune cells. Strategies that achieve this goal will define the success of immunotherapy in ovarian cancer and profoundly impact clinical outcome in patients. Based on our exciting data, we hypothesize that ZNF217 depletion will remodel ovarian tumors and convert them into tumors that is infiltrated with immune cells. Therefor
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310351
Entities
People
- Achuth Padmanabhan
Organizations
- United States Army
- University of Maryland