Novel immunological biomarkers ovarian cancer prognosis

 描述(由申请人提供)：上皮性卵巢癌(EOC)在美国和世界范围内仍然是一个严重的公共卫生问题。虽然许多努力都集中在为卵巢癌患者提供新的治疗方法上，但在过去的几十年里，卵巢癌的死亡率并没有明显改善。人们对开发新的免疫治疗策略越来越感兴趣，这需要相关研究来确定最有可能从这些治疗中受益的靶点和患者。在拟议的研究中，我们打算研究以前未探索的免疫标记物作为侵袭性浆液性卵巢癌患者预后的预测因子。我们的初步结果显示，在晚期卵巢癌患者中，细胞损伤的线粒体产物被释放到细胞外环境中，在那里它们激活中性粒细胞。这些受刺激的中性粒细胞产生反应性氧化剂和中性粒细胞胞外陷阱(Net)，这是一种独特的中性粒细胞死亡模式，其特征是细胞膜破裂，DNA、组蛋白和蛋白酶在细胞外释放。虽然Net的功能是抵御感染，但在肿瘤微环境中，它们有望促进侵袭和转移。我们将研究线粒体DNA(MtDNA)，作为衡量线粒体损伤相关分子模式(DAMP)的指标，以及它们与侵袭性浆液性卵巢癌患者Net的关系。在特定的目标1中，我们建议评估配对的治疗前血清和腹水样本中mtDNA水平在预测晚期浆液性卵巢癌患者第一年内复发、PFS和OS中的作用。在具体目标2中，我们将评估血液、腹水和肿瘤中中性粒细胞和网络标志物在侵袭性浆液性卵巢癌预后中的作用。在具体目标3中，我们打算为晚期浆液性卵巢癌患者开发一种新的预后标志，该标志结合了mtDNA、网络标记物和标准预后变量的独立和联合作用。为了实现这些具体目标，我们将利用和扩大现有的协作基础设施，用于样本收集和银行程序，以支持对平机会新的预后生物标志物的评估。我们将利用罗斯韦尔公园癌症研究所(RPCI)目前招募的一组患者来开发预后标志，匹兹堡大学癌症研究所(UPCI)登记的接受类似治疗的患者将成为特定目标3发现的独立验证队列。这些目标的实现将为EOC的预后建立新的基于免疫的生物标志物，并可能为免疫治疗的新靶点奠定基础。

 DESCRIPTION (provided by applicant): 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.