(PQD2)New Biomarkers and Pathways to Enhance Cure in Ovarian Cancers

描述（由申请人提供）：浆液性卵巢癌（SOC）在上皮癌中是不常见的，因为一些（10-15%）在第3和第4阶段可以通过化疗治愈。SOC是复杂的实体，其中癌细胞与免疫、炎症、血管和基质细胞之间发生病理共生相互作用。我们建议在许多恶性和正常细胞类型的单细胞水平上研究SOC的蛋白质组学谱，包括可以在治疗后重新建立完整肿瘤细胞层次的肿瘤起始细胞群。多维（每个细胞>40个参数）质谱细胞术提供了前所未有的机会来同时测量构成肿瘤的多种细胞类型中的这些反应，并且在这样做时，鉴定与离体药物敏感性和抗性相关的途径和机制。因此，我们将评估卡铂（PT）、紫杉醇（TX）和选择性途径抑制剂的基础和药物诱发的蛋白质组特征。SOC的主要挑战是通过初始PT和TX增强治愈。我们的目标是确定PT、TX和PT/TX新组合的预测性治疗生物标志物。其目标是：（1）利用质谱细胞术鉴定指定SOC药物敏感和耐药细胞模型对PT、TX和两种潜在致敏途径（IAP和CCL 2/CCR 2）的相对响应性的蛋白质组谱。该目标将利用来自6个亲本系的12个耐药细胞模型。在我们的初步数据中，IAP和CCL 2抑制增强了PT和TX的功效。将用PT和TX评价抑制剂组合促进细胞死亡的能力 在细胞模型和异种移植物中的肿瘤消退。(2)在SOC临床标本中检测这些蛋白质组学特征和治疗靶点。我们现有一个超过50个标本的可存活冷冻SOC肿瘤库，并计划在本项目期间研究总共90个。将使用来自选定临床标本的异种移植物评估体内药物反应性，收获肿瘤进行质谱细胞计数测定。(3)使用SOC细胞模型和临床标本的突变分析和表达谱进行基因组研究。这些将结合TCGA和Tothill数据库进行分析，应用新型计算工具将质谱细胞术分析与转录组学，表观遗传学和外显子组数据库相结合。基因组分析将有助于鉴定质谱细胞术的新候选治疗生物标志物，以及PT/TX组合的其他治疗靶点。该项目的科学益处将是通过功能蛋白质组学和分子水平上的药物反应性决定因素对SOC可治愈性的新见解。对患者的预期益处是能够在诊断时识别应答者，新的药物组合导致新的临床试验，并为个体患者前瞻性地定制治疗。

DESCRIPTION (provided by applicant): Serous ovarian cancers (SOCs) are unusual among epithelial cancers in that some (10-15%) are curable by chemotherapy in stages 3 and 4. SOCs are complex entities in which a pathologically symbiotic interplay occurs between cancer cells and immune, inflammatory, vascular and stromal cells. We propose to study proteomic profiles of SOCs at the single-cell level in many malignant and normal cell types, including tumor-initiating cell populations that can re-establish a complete tumor cell hierarchy post treatment. Multi-dimensional (>40 parameters per cell) mass cytometry affords unprecedented opportunities to measure these responses simultaneously in the multiple cell types that comprise the tumor and, in so doing, to identify pathways and mechanisms associated with ex vivo drug sensitivity and resistance. Thus, we will assess both basal and drug-evoked proteomic signatures for carboplatin (PT), paclitaxel (TX) and selective pathway inhibitors. A major challenge in SOC is to enhance cure by initial PT and TX. Our goals are to identify predictive therapeutic biomarkers for PT, TX, and novel combinations with PT/TX. The aims are: (1) Utilize mass cytometry to identify proteomic profiles that designate the relative responsiveness of SOC drug-sensitive and resistant cell models to PT, TX, and two potential sensitizing pathways: IAPs and CCL2/CCR2. This aim will utilize 12 drug-resistant cell models derived from 6 parental lines. In our preliminary data, IAP and CCL2 inhibition enhances the efficacy of PT and TX. Combinations of inhibitors will be evaluated with PT and TX for their ability to promote cell death in the cell models and tumor regression in xenografts. (2) Validate these proteomic profiles and therapeutic targets in SOC clinical specimens. We have an existing viably frozen SOC tumor bank of more than 50 specimens and plan to study a total of 90 during this project. Xenografts from selected clinical specimens will be utilized to assess drug responsiveness in vivo, with harvesting of tumors for mass cytometric assays. (3) Perform genomic studies using mutation analyses and expression profiles of the SOC cell models and clinical specimens. These will be analyzed in conjunction with the TCGA and Tothill databases, applying novel computational tools for combining mass cytometry analysis with transcriptomic, epigenetic and exomic databases. The genomic analyses will facility the identification of new candidate therapeutic biomarkers for mass cytometry, as well as additional therapeutic targets for PT/TX combinations. The scientific benefits of this project will be new insights into SOC curability via determinants of drug responsiveness at the functional proteomic and molecular level. The expected benefits to patients are the ability to identify responders at diagnosis, new drug combinations leading to new clinical trials, and tailoring therapies prospectively for individual patients.