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

上皮性卵巢癌(EOC)是最致命的妇科恶性肿瘤，超过2万例 在美国，每年新诊断的病例和超过13,000人死亡。不幸的是，在那里 自30多年来引入基于铂的疗法以来，存活率几乎没有变化 那是以前的事了。因为寻找更新、更有效的药物并没有取得丰硕的成果，也没有进行积极的手术 此外，以铂为基础的化疗仍然是该病的标准一线治疗方法。然而， 个体对铂治疗的反应是高度可变和不可预测的。最终，大多数 女性会患上耐铂的疾病并死于这种疾病。没有办法确定谁会做出回应 以铂为基础的治疗效果较差；也没有任何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记物，提供早期迹象 疗效，支持患者治疗分层，并提出改善治疗的干预措施 应对和生存是迫切需要的。EOC和其他固体中的基础癌症研究发现 肿瘤提示肠道细菌通过以下方式影响女性对铂类药物的反应 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，目前还没有关于肠道的人体研究 细菌与EOC治疗反应，也不影响肠道细菌、TME免疫和 治疗反应和结果。 我们在新诊断的卵巢癌妇女中的初步发现支持动物模型数据。后盾为 根据实验室研究数据和我们在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记物，将导致更好的患者分层。 在目标1中，我们将评估104例新诊断的卵巢癌患者的肠道微生物组和系统代谢组。 确定预测铂类治疗反应和结果的肠道细菌的病例。在AIM 2我们将使用免疫图谱分析来评估TME免疫渗透和免疫基因表达 在我们的队列中。然后我们将使用高维基因组、新陈代谢和转录组数据 根据AIMS 1和AIMS 2生成，以确定与以下各项相关的有利和不利肠道微生物群 治疗反应、结果和局部肿瘤免疫。我们还将鉴定出肠道细菌可以 作为干预目标，以提高治疗效果或阻止癌症进展。我们的团队 将很好地进行人体试验以评估改变肠道细菌的影响 关于平等机会结果的组成。我们也将处于有利地位，继续进行机械学研究，以 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。该提案使用了来自以前资助的NCI项目的现有生物检疫试剂，以及 临床注释数据以生成高维、多组数据，以便开发 用于患者选择或分层的预测和预后生物标记物。

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.