Abstract 1418: Exosomes in predicting response to chemotherapy in endometrial carcinoma

Abstract Background: Endometrial cancer is the most common gynecologic malignancy and incidence and mortality continue to increase. While active chemotherapy regimens are available, the median time to progression remains six to eight months and mortality in this setting is approaches 100%. Rapid progression and lack of response to systemic therapies are significant challenges in this disease and underscore the need for identification of molecular markers and targets of drug resistance. Alterations in non-coding micro-RNA (miRNA) have been shown to be necessary for cellular proliferation and differentiation in normal and malignant phenotypes. miRNA signatures unique to malignant, specifically treatment resistant cancers are described in many solid tumors; however, knowledge of these changes in resistant endometrial cancer is limited. Identification of molecular signatures unique to drug resistant endometrial cancer may inform novel therapeutic targets to predict and/or reverse resistance to chemotherapy. One source of tumor miRNA is in exosomes derived from tumor cells that transport tumor derived products including non-coding RNAs. They are readily identified in peripheral body fluids and are known to act at distant sites to facilitate tumor growth and metastasis. As such, exosomes are a potential source of tumor-specific genetic material that may characterize disease and predict drug response. Results: In characterized endometrial cancer cell lines, we determined chemo-sensitivity to platinum-based therapy. Exosomes were isolated and purified from the culture media and exosomal miRNA profiles were sequenced, aligned and cross-referenced with published datasets. Our preliminary data have identified a unique exosomal miRNA signature that differentiates chemotherapy sensitive and resistant endometrial cancer in vitro. Upregulation of oncomirs, miR155, miR98 and downregulation of tumor suppressor miRNAs, miR25, miR27a, miR200a were observed. Two unique miRNA candidates were also identified miR3125 and miR6068. The clinical expression of these candidate miRNAs was interrogated within the Kaplan Meier plotter RNAseq dataset and decreased overall survival was observed in samples exhibiting dysregulation of the candidate miRNA panel1. These results were confirmed in vitro with rtPCR. We have since isolated exosomes from the sera of 14 endometrial cancer patients with known clinical outcomes data. Seven patients exhibited rapid disease progression on standard chemotherapy while 7 demonstrated a complete clinical response of at least 6 months. The exosomal miRNA was isolated, quantified and sequencing is ongoing. Conclusions: Our data implicate a unique grouping of miRNAs in the endometrial cancer chemo-resistance. The clinical impact of these miRNAs remains unknown, but 5 are associated with a significant decrease in overall survival1. The ability to detect a unique miRNA profile in the body fluids of patients, provides an accessible resource for study before and during treatment. Such data could significantly impact treatment of endometrial cancer both as a predictive biomarker of response and source of novel therapeutic targets. The high rate of recurrence, inevitable development of a chemo-resistant disease and the clinical challenges associated with repeated tumor sampling, make exosomal miRNA a valuable candidate for exploration in this disease. Citation Format: Katherine M. Moxley. Exosomes in predicting response to chemotherapy in endometrial carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1418.