(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）在上皮性癌症中是不寻常的，因为一些（10-15%）在3期和4期可以通过化疗治愈。肿瘤细胞是一种复杂的实体，其中癌细胞与免疫细胞、炎症细胞、血管细胞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SOCs的蛋白质组学特征，包括肿瘤启动细胞群，这些细胞群可以在治疗后重建完整的肿瘤细胞结构。多维（每个细胞40个参数）质量细胞术提供了前所未有的机会，可以同时测量构成肿瘤的多种细胞类型的这些反应，并在此过程中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发的蛋白质组学特征。SOC的一个主要挑战是通过初始PT和TX来提高治愈率。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。目的是：(1)利用质细胞术鉴定SOC药物敏感和耐药细胞模型对PT、TX和两种潜在致敏途径（IAPs和CCL2/CCR2）的相对反应性的蛋白质组学特征。该目的将利用来自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。抑制剂组合将与PT和TX一起评估其促进细胞死亡的能力

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.