Abstract 559: Investigating DDX3X as a target to improve outcomes in Black and Native American endometrial cancer patients

Abstract

Abstract Introduction: The goal of this project was to identify and test a new molecular target that will help reduce the worse outcomes of endometrial cancer, especially in Black and Native American patients. Endometrial cancer is rapidly on the rise in the developed world. It has overtaken many other types of cancer in both incidence and mortality. Black populations are disproportionately impacted by endometrial cancer, both in Oklahoma and across the United States. In Oklahoma specifically, Native Americans are the most heavily impacted group. Methods: Machine learning techniques were used to analyze comprehensive metabolic panel (CMP) data from electronic medical record of patients in the University of Oklahoma (OU) network of hospitals and clinics. This data was broken down by endometrial cancer status, race, and age. Plasma samples of endometrial cancer patients were collected from the OU Health Sciences Center Biobank. These samples were analyzed by mass spectrometry. Endometrial cancer cell lines Ishikawa (low-grade) and ARK-1 and ARK-4 (high grade) were cultured in EMEM. For treating the cells, we used RK-33, a small molecule inhibitor of DDX3X. MTT assays were performed in 96-well plates at increasing concentrations of RK-33 for 48 hours. Western blots were used to determine effect of the drug on cellular DDX3X and yH2AX protein levels. Results: Machine learning analysis EMR data revealed a difference between races in albumin levels of women with endometrial cancer. Black and Native American patients had lower albumin, which is known to correlate to worse outcomes. IPA analysis of plasma proteomics revealed several proteins that were differentially expressed between races. Among these was DDX3X, the X-linked form of DDX3, a DEAD-box RNA helicase which is involved in DNA damage repair. Patient data indicated that patients with high DDX3X expression tended to have lower survival rates. MTT analysis determined that Ishikawa has a lower IC50 than the high-grade cell lines, but all responded. Western blotting confirmed that treatment with RK-33 reduced the amount of DDX3X in the cells and increased y-H2AX, indicating more DNA damage. Conclusions: This study demonstrates that DDX3X is a valid molecular target in endometrial cancer. The differential expression across race groups indicates that Black and Native Americans may stand to benefit the most from a novel drug targeting this difference. Because DDX3X is involved in DNA damage repair, combining the treatment with a DNA-damaging drug may increase response to the drug as well. Citation Format: James D. Lausen, Doris M. Benbrook. Investigating DDX3X as a target to improve outcomes in Black and Native American endometrial cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 559.