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

描述(申请人提供)：浆液性卵巢癌(SOC)在上皮性癌症中很少见，因为有些(10%-15%)可以通过3期和4期的化疗治愈。SOC是一种复杂的实体，其中癌细胞与免疫、炎症、血管和基质细胞之间发生病理上的共生相互作用。我们建议在单个细胞水平上研究许多恶性和正常细胞类型的SOC的蛋白质组学特征，包括能够在治疗后重建完整的肿瘤细胞层级的肿瘤起始细胞群。多维(每细胞40个参数)质量细胞术提供了前所未有的机会，可以在构成肿瘤的多种细胞类型中同时测量这些反应，从而确定与体外药物敏感性和耐药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导的蛋白质组特征。SOC中的一个主要挑战是通过初始PT和TX来加强治愈。我们的目标是确定PT、TX的预测性治疗生物标记物，以及PT/TX的新组合。其目的是：(1)利用质量细胞术鉴定蛋白质组图谱，确定SOC药物敏感和耐药细胞模型对PT、TX和两种潜在的增敏途径：IAPS和CCL2/CCR2的相对反应性。这一目标将利用来自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CCL2抑制增强了PT和TX的疗效。将用PT和TX评估抑制剂的组合促进细胞死亡的能力 在异种移植的细胞模型和肿瘤消退中。(2)在SOC临床标本中验证这些蛋白质组图谱和治疗靶点。我们有一个现有的50多个标本的活体冷冻SOC肿瘤库，并计划在这个项目期间总共研究90个标本。来自选定临床标本的异种移植将被用来评估体内的药物反应，并采集肿瘤进行质量细胞分析。(3)利用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。这些将与TCGA和Tothill数据库一起进行分析，应用新的计算工具将质量细胞术分析与转录组、表观遗传学和外显组数据库相结合。基因组分析将有助于识别新的候选治疗生物标记物，用于质量细胞分析，以及PT/TX联合治疗的额外治疗靶点。该项目的科学益处将是通过在功能蛋白质组和分子水平上的药物响应性决定因素对SOC可治愈性的新见解。对患者的预期好处是能够在诊断时识别响应者，导致新的临床试验的新药组合，以及前瞻性地为个别患者量身定做治疗方法。

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.