Exosomes in Predicting Response to Chemotherapy in Metastatic Endometrial Carcinoma Abstract: Endometrial carcinoma represents the most common gynecologic malignancy in the US affecting 60,000 women annually. Early stage cancers are curable, but the treatment of metastatic disease remains challenging. The most active standard therapy is a platinum-taxane combination which yields response rates of 55-60%. Despite this, drug resistance develops readily with median time to survival of only six to eight months. The rapid progression and lack of therapeutic response to both cytotoxic and targeted therapy represent treatment challenges unique to this highly lethal disease state and underscore the need for identification of molecular targets of drug resistance. Molecular alterations in tumor biology that develop during the course of chemotherapy, particularly those that predict treatment failure, remain unknown. Alterations in the protein expression unique to cancers are implicated in tumorigenesis and drug resistance across malignancies. Changes in non-coding RNA and downstream protein products necessary for cellular proliferation and differentiation develop under the stress of chemotherapy in many solid tumors. Limited knowledge of the molecular derangements in advanced endometrial cancer exist at present. Identification of molecular signatures unique to drug resistant endometrial cancer may facilitate identification of novel therapeutic targets to predict and/or reverse resistance to chemotherapy. Exosomes derived from tumor cell membranes serve as transport vehicles for a variety of tumor derived products including DNA, coding and non-coding RNA and proteins. Exosomes can be identified in peripheral body fluids in large quantities and act at distant sites to facilitate tumor growth and metastasis. They bear direct resemblance to the tumor cells or origin and reflect ongoing alterations in the tumor cell environment. As such, they represent potential peripheral biomarkers of disease and drug resistance. We hypothesize that exosome- derived miRNA signatures will reveal molecular mechanisms of drug-resistance in endometrial cancer and that the isolation of these exosomes in the peripheral blood of patients undergoing chemotherapy will provide insight into the therapeutic targets critical to overcoming chemotherapy resistance.
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