Novel immunological biomarkers ovarian cancer prognosis

卵巢癌预后的新型免疫生物标志物

• 批准号: 8896245
• 负责人: KIRSTEN B. MOYSICH
• 金额: $ 58.97万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896245
• 关键词: Acceleration; Apoptosis; Area; Ascites; Biological Markers; Blood; Cancer Patient; Cancer Prognosis; Cell Death; Cell Hypoxia; Cells; Cessation of life; Correlative Study; DNA; Endothelial Cells; Enrollment; Environment; Epithelial ovarian cancer; Evaluation; Foundations; Generations; Histones; Host Defense; Human; Immune; Immune response; Immunologic Markers; Immunologics; Immunotherapeutic agent; Immunotherapy; Individual; Infection; Inflammation; Inflammatory; Injury; Leukocyte Elastase; Malignant Neoplasms; Malignant neoplasm of ovary; Matrix Metalloproteinases; Measures; Mediating; Membrane; Microbe; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Myeloid Cells; Necrosis; Neoplasm Metastasis; Neutrophil Activation; Neutrophil Infiltration; Operative Surgical Procedures; Outcome; Oxidants; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Peptide Receptor; Peptides; Procedures; Process; Prognostic Marker; Progression-Free Survivals; Public Health; Recruitment Activity; Refractory Disease; Relapse; Relative (related person); Research; Research Infrastructure; Resected; Role; Roswell Park Cancer Institute; Sampling; Sepsis; Serous; Serum; Shapes; Stretching; TLR9 gene; Testing; Thrombosis; Tissues; Tumor Cell Invasion; University of Pittsburgh Cancer Institute; Validation; Woman; angiogenesis; antimicrobial; base; cohort; extracellular; improved; interest; macrophage; microbial; mortality; mouse model; neoplastic cell; neutrophil; novel; novel therapeutic intervention; outcome forecast; pathogen; prognostic; public health relevance; receptor; sample collection; therapeutic target; tumor; tumor microenvironment; tumor progression

 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.

 描述（由申请人提供）：上皮性卵巢癌（EOC）仍然是美国和全世界的一个重大公共卫生问题。尽管人们在针对 EOC 患者的新治疗方法上投入了大量精力，但在过去几十年中，EOC 死亡率并未显着改善。人们对开发新型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疗法中受益的靶标和患者。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 EOC 患者预后的预测因子。我们的初步结果表明，在晚期 EOC 患者中，细胞损伤的线粒体产物被释放到细胞外环境中，并在其中激活中性粒细胞。这些受刺激的中性粒细胞产生活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，其特征是膜破裂和 DNA、组蛋白和蛋白酶片段的胞外释放。虽然NETs具有防御感染的功能，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)，作为线粒体损伤相关分子模式 (DAMP) 的衡量标准，及其与侵袭性浆液性 EOC 女性中 NET 的关系。我们在具体目标 1 中建议评估配对治疗前血清和腹水样本中 mtDNA 水平在预测晚期浆液性 EOC 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、腹水和肿瘤中的中性粒细胞和 NET 标记物在侵袭性浆液性 EOC 结果中的作用。在具体目标 3 中，我们打算为晚期浆液性 EOC 患者开发一种新的预后特征，其中结合了 mtDNA、NET 标记和标准预后变量的独立和组合效应。为了实现这些具体目标，我们将利用并扩展已建立的样本收集和银行程序协作基础设施，以支持 EOC 新型预后生物标志物的评估。我们将利用目前在罗斯威尔帕克癌症研究所 (RPCI) 招募的一组患者来开发预后特征，而在匹兹堡大学癌症研究所 (UPCI) 招募的接受类似治疗的患者将成为特定目标 3 中研究结果的独立验证队列。这些目标的实现将为 EOC 预后建立新的基于免疫的生物标志物，并可能为 EOC 的新目标奠定基础。 免疫疗法。