Epithelial ovarian cancer (EOC) remains a significant public health problem in the US and worldwide. While a great deal of effort has focused on new therapeutic approaches for EOC patients, EOC mortality rates have not markedly improved over the past decades. There is increasing interest in developing novel immunotherapeutic strategies, which require correlative studies to identify targets and patients who are most likely to benefit from these therapies. In the proposed study, we intend to study previously unexplored immune markers as predictors for outcomes among invasive serous EOC patients. Our preliminary results show that in patients with advanced EOC, mitochondrial products of cellular damage are released into the extracellular environment where they activate neutrophils. These stimulated neutrophils generate reactive oxidants and neutrophil extracellular traps (NETs), a distinct mode of neutrophil death characterized by breakdown of membranes and extracellular release of stretches of DNA, histones, and proteases. While NETs function to defend against infection, in the tumor microenvironment, they are expected to facilitate invasion and metastasis. We will study mitochondrial DNA (mtDNA), as a measure of mitochondrial damage-associated molecular patterns (DAMPs) and their relationship to NETs in women with invasive serous EOC. We propose in Specific Aim 1 to evaluate the role of mtDNA levels in paired pre-treatment serum and ascites samples in predicting relapse within the first year, PFS and OS in patients with advanced serous EOC.
In Specific Aim 2, we will evaluate the role of neutrophils and NET markers in blood, ascites and tumors in invasive serous EOC outcomes.
In Specific Aim 3, we intend to develop a new prognostic signature for patients with advanced serous EOC that incorporates the independent and combined effects of mtDNA, NET markers, and standard prognostic variables. To accomplish these Specific Aims, we will take advantage of, and expand on, an established collaborative infrastructure for sample collection and banking procedures to support evaluation of novel prognostic biomarkers for EOC. We will utilize a cohort of patients currently being recruited at Roswell Park Cancer Institute (RPCI) to develop the prognostic signature, and similarly treated patients being enrolled at the University of Pittsburgh Cancer Institute (UPCI) will be an independent validation cohort for findings in Specific Aim 3. Accomplishment of these aims will establish novel immune-based biomarkers for prognosis in EOC, and may create the foundation for new targets for immunotherapy.
The proposed research will study previously unexplored immune markers in the prognosis of epithelial ovarian cancer. If the prognostic significance of these markers can be established and validated, our results will have significant translational potential for the identification of patients who are likely to fail standard therapy and for identifying promising targets for immunotherapy.
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