Multi-omic Predictive Markers for Ovarian Cancer Therapy Response and Outcomes

卵巢癌治疗反应和结果的多组学预测标记

基本信息

批准号：
10678828
负责人：
FRANCESMARY MODUGNO
金额：
$ 14.63万
依托单位：
MAGEE-WOMEN'S RES INST AND FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-08 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10678828
关键词：
16S ribosomal RNA sequencing Acceleration Affect Aftercare Animal Model Bacteria Basic Cancer Research Basic Science Bioinformatics Biological Assay Biological Markers Biological Specimen Banks Blood Cancer Prognosis Cessation of life Classification Clinical Combination immunotherapy Data Disease Disease Resistance Epithelial ovarian cancer Funding Gene Expression Genomics Growth Human Immune Immune response Immunity Immuno-Chemotherapy Immunotherapy In Vitro Intervention Laboratory Research Localized Malignant Neoplasm Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Metabolic Pathway Metagenomics Multiomic Data Mus New Agents Newly Diagnosed Operative Surgical Procedures Outcome Patient Selection Patients Platinum Population Positioning Attribute Prediction of Response to Therapy Prognostic Marker Progression-Free Survivals Resistance Sampling Serum Shotgun Sequencing Solid Neoplasm Specimen Testing Translating Treatment Efficacy Treatment Protocols Treatment outcome Tumor Immunity Tumor Tissue United States Woman biomarker validation cancer therapy chemotherapy cohort conventional therapy cytotoxicity data modeling experience gastrointestinal epithelium gut bacteria gut microbiome high dimensionality immune cell infiltrate improved improved outcome individual response metabolome metabolomics microbial composition microbiome multiple omics patient stratification personalized medicine predicting response predictive marker research study response standard care success therapy outcome transcriptomics treatment response treatment stratification tumor tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, with more than 20,000 newly- diagnosed cases and over 13,000 deaths in the United States each year. Unfortunately, there has been little change in survival since platinum-based therapies were introduced over 30 years ago. Because the search for newer, more effective agents has not been fruitful, aggressive surgery plus platinum-based chemotherapy remains the standard first-line treatment of the disease. However, individual response to platinum therapy is highly variable and unpredictable. Eventually, most women develop and succumb to platinum-resistant disease. No way exists to identify who will respond poorly to platinum-based therapy; nor are there any clinically-validated interventions to improve therapy response. Biomarkers that can predict therapy response, provide an early indication of efficacy, support patient treatment stratification, and suggest interventions to improve therapy response and survival are urgently needed. Basic cancer research discoveries in EOC and other solid tumors suggest that gut bacteria impact how a woman responds to platinum-based therapy by influencing the local tumor microenvironment (TME). Thus, gut bacteria may serve as predictive biomarkers of therapy response and outcome. However, there have been no human studies of gut bacteria and EOC therapy response, nor on the interactions among gut bacteria, TME immunity, and treatment response and outcome. Our preliminary findings in women with newly-diagnosed EOC support the animal model data. Backed by the laboratory research data and based on our preliminary findings in an EOC population, we propose to develop predictive microbiome-based biomarkers that will lead to better patient stratification. In Aim 1, we will assess the gut microbiome and systemic metabolome in 104 newly diagnosed EOC cases to identify gut bacteria predictive of response and outcome to platinum-based therapy. In Aim 2 we will use immune-profiling assays to assess TME immune infiltrates and immune gene expression in our cohort. We will then use the high- dimensional genomic, metabolomic and transcriptomic data generated from Aims 1 and 2 to identify favorable and unfavorable gut microbiomes associated with therapy response, outcomes, and local tumor immunity. We will also identify gut bacteria that can serve as intervention targets to improve therapy efficacy or block cancer progression. Our team will then be well positioned to conduct human trials to assess the effects of altering gut bacteria composition on EOC outcomes. We will also be well positioned to pursue mechanistic studies to illuminate how gut bacteria impact therapy response and outcome, thus further identifying treatment targets. This proposal uses existing biospecimens from previously-funded NCI projects together with clinical annotating data to generate high-dimensional, multi-omic data in order to develop predictive and prognostic biomarkers for patient selection or stratification.

上皮性卵巢癌 (EOC) 是最致命的妇科恶性肿瘤，有超过 20,000 例美国每年新诊断病例和死亡人数超过 13,000 人。不幸的是，有自铂类疗法推出 30 年来，生存率几乎没有变化前。由于寻找更新、更有效的药物尚未取得成果，积极的手术加铂类化疗仍然是该疾病的标准一线治疗方法。然而，个体对铂类治疗的反应变化很大且不可预测。最终，大多数女性会患上铂耐药性疾病并死于这种疾病。无法确定谁会做出回应对铂类治疗效果不佳；也没有任何经过临床验证的干预措施可以改善治疗反应。可以预测治疗反应的生物标志物，提供早期指示疗效，支持患者治疗分层，并建议改善治疗的干预措施迫切需要响应和生存。 EOC 和其他固体的基础癌症研究发现肿瘤表明肠道细菌通过以下方式影响女性对铂类治疗的反应影响局部肿瘤微环境（TME）。因此，肠道细菌可以作为预测治疗反应和结果的生物标志物。然而，目前还没有针对肠道的人体研究细菌和 EOC 治疗反应，也不涉及肠道细菌、TME 免疫和治疗反应和结果。我们对新诊断的 EOC 女性的初步研究结果支持动物模型数据。支持者实验室研究数据并根据我们在 EOC 人群中的初步发现，我们建议开发基于微生物组的预测生物标志物，这将导致更好的患者分层。在目标 1 中，我们将评估 104 名新诊断的 EOC 的肠道微生物组和全身代谢组案例来识别肠道细菌，以预测铂类治疗的反应和结果。瞄准 2 我们将使用免疫分析测定来评估 TME 免疫浸润和免疫基因表达在我们的队列中。然后我们将使用高维基因组、代谢组和转录组数据根据目标 1 和 2 生成，以确定与以下疾病相关的有利和不利的肠道微生物组：治疗反应、结果和局部肿瘤免疫。我们还将鉴定可以作为提高治疗效果或阻止癌症进展的干预目标。我们的团队然后将能够进行人体试验以评估改变肠道细菌的影响 EOC 结果的组成。我们也将处于有利地位进行机制研究阐明肠道细菌如何影响治疗反应和结果，从而进一步确定治疗方法目标。该提案使用了先前资助的 NCI 项目的现有生物样本以及临床注释数据以生成高维、多组学数据，以便开发用于患者选择或分层的预测和预后生物标志物。