Omic and Multidimensional Spatial Atlas of Metastatic Breast and Prostate Cancers

转移性乳腺癌和前列腺癌的组学和多维空间图谱

• 批准号: 9788351
• 负责人: JOE W. GRAY
• 金额: $ 175.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788351
• 关键词: 3-Dimensional; ATAC-seq; Adopted; Aftercare; Antigen Presentation; Area; Atlases; Biological Assay; Biological Process; Biopsy; Biopsy Specimen; Blood; Blood specimen; CDK4 gene; Castration; Cells; Chemicals; Chromatin; Clinical; Collection; Computer software; Core Biopsy; Data; Data Analyses; Development; Diagnostic Procedure; Electron Microscope; Ensure; Evaluation; Event; Extracellular Matrix; Formalin; Freezing; Future; Generations; Genes; Genomic Instability; Genomics; Goals; Image; Image Analysis; Imagery; Immune; Immune checkpoint inhibitor; Immunofluorescence Immunologic; Immunohistochemistry; Immunomodulators; Ions; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Measurement; Mechanics; Metastatic breast cancer; Modality; Molecular; Paraffin Embedding; Pathway interactions; Patients; Periodicity; Pharmaceutical Preparations; Plant Resins; Primary Neoplasm; Private Sector; Procedures; Process; Production; Prostate Cancer therapy; Quality Control; Reproducibility; Resistance; Resolution; Sampling; Scanning; Scanning Electron Microscopy; Scientist; Signal Transduction; Specimen; Speed; Structure; System; Technology; Therapeutic; Three-Dimensional Image; Time; Tissue Preservation; Tissues; Tumor-Derived; Visualization software; Work; base; biological systems; cancer cell; cohort; combinatorial; cost; drug efficacy; epigenomics; exhaustion; hormone receptor-positive; hormone therapy; immune checkpoint; immune resistance; indexing; individual patient; inhibitor/antagonist; malignant breast neoplasm; molecular imaging; nanoscale; neoplastic cell; next generation; novel diagnostics; novel therapeutic intervention; operation; paraform; preservation; programs; prospective; resistance mechanism; single cell sequencing; targeted treatment; tool; triple-negative invasive breast carcinoma; tumor

ABSTRACT - Overall We propose to create an Omic and Multidimensional Spatial (OMS) Atlas that will enable discovery of mechanisms of resistance that arise in individual patients with metastatic breast and prostate cancer during treatment with current generation targeted therapeutic combinations and immune checkpoint inhibitors. The OMS Atlas is motivated by the fact that these treatments typically are only transiently effective in the metastatic setting. Possible resistance mechanisms may be intrinsic to the tumor cells or derive from the diverse microenvironments in which the tumor cells live. The OMS Atlas will focus on elucidating these resistance mechanisms in three specific current generation clinical scenarios: (a) hormone-receptor positive breast cancer (HRBC) undergoing treatment with a CDK4/6 inhibitor in combination with endocrine therapy, (b) triple negative breast cancer (TNBC) undergoing treatment with a PARP inhibitor and an immunomodulatory agent, and (c) castration resistance prostate cancer (CRPC) undergoing treatment with enzalutamide. We will accomplish this through work in four areas. A Biospecimen Unit will prospectively collect, manage, and distribute longitudinal clinical information, blood, and biopsies from 20 patients from each of two metastatic breast cancer cohorts and one prostate cancer cohort that will be analyzed to create three OMS Atlases. The biopsies will be preserved to enable analyses using multiple characterization modalities. A Characterization Unit will analyze (a) OCT frozen specimens using Topographic Single Cell Sequencing (TSCS) and Single-cell Combinatorial Indexing ATAC- seq (sci-ATAC-seq) to elucidate spatially defined genomic changes and chromatin accessibility in single cells, (b) formalin fixed, paraffin embedded (FFPE) specimens using multiplex immunohistochemistry (mIHC) to assess the immune microenvironment and cyclic Immunofluorescence (cycIF) to assess the composition and molecular states of tumor cells and their microenvironments, and (c) paraformaldehyde fixed, resin embedded (PFRE) specimens using a Focused Ion Beam Scanning Electron Microscope (FIB-SEM) to identify ultrastructural changes in 2D images and targeted 3D images with 4-nm resolution. Omic characterization of the same tumor samples will be provided by the SMMART Program. A Data Analysis Unit will develop and deploy tools to (a) manage, analyze, and visualize Tier 1 data comprised of raw sequence data and images to generate unimodal Tier 2 results, (b) integrate omics and imaging data through crosswise mapping to create single timepoint tumor maps and quantify systems biological functions of tumor cellular subpopulations to generate Tier 3 results, and (c) explore differences between pre- and on/post-treatment tumor maps to reveal mechanisms of resistance that comprise Tier 4 results. We will collaborate with private sector partners to evaluate and adopt next generation technologies that increase analytical power and speed and reduce costs. The Administrative Unit will facilitate the coordination, operation, interaction, and evaluation of activities within the OMS Atlas and between OMS Atlas scientists and the HTAN.

摘要 - 总体 我们建议创建一个组学和多维空间（OMS）图集，以便发现 转移性乳腺癌和前列腺癌个体患者在治疗过程中出现的耐药机制 使用当前一代靶向治疗组合和免疫检查点抑制剂进行治疗。这 OMS Atlas 的动机是这些治疗通常仅对转移性肿瘤短暂有效。 环境。可能的耐药机制可能是肿瘤细胞固有的或源自不同的机制。 肿瘤细胞生存的微环境。 OMS Atlas 将重点阐明这些阻力 当前三种特定临床情况的机制：(a) 激素受体阳性乳腺癌 (HRBC) 接受 CDK4/6 抑制剂联合内分泌治疗，(b) 三阴性 正在接受 PARP 抑制剂和免疫调节剂治疗的乳腺癌 (TNBC)，以及 (c) 正在接受恩杂鲁胺治疗的去势抵抗性前列腺癌（CRPC）。我们将完成这个 通过四方面工作。生物样本单位将前瞻性地收集、管理和分发纵向样本 来自两个转移性乳腺癌队列各 20 名患者的临床信息、血液和活检 一组前列腺癌队列将被分析以创建三个 OMS 图集。活检组织将保存至 使用多种表征模式进行分析。表征单元将分析 (a) 冷冻 OCT 使用地形单细胞测序 (TSCS) 和单细胞组合索引 ATAC- seq (sci-ATAC-seq) 阐明单细胞中空间定义的基因组变化和染色质可及性， (b) 使用多重免疫组织化学 (mIHC) 福尔马林固定、石蜡包埋 (FFPE) 标本 评估免疫微环境和循环免疫荧光 (cycIF) 以评估成分和 肿瘤细胞的分子状态及其微环境，以及（c）多聚甲醛固定、树脂包埋 (PFRE) 样本使用聚焦离子束扫描电子显微镜 (FIB-SEM) 来识别 2D 图像和 4 nm 分辨率的目标 3D 图像中的超微结构变化。组学表征 SMMART 计划将提供相同的肿瘤样本。数据分析部门将开发和部署 用于 (a) 管理、分析和可视化由原始序列数据和图像组成的第 1 层数据的工具 单峰第 2 层结果，(b) 通过交叉映射整合组学和成像数据以创建单一 时间点肿瘤图谱并量化肿瘤细胞亚群的系统生物学功能以生成 Tier 3 结果，以及（c）探索治疗前和治疗中/治疗后肿瘤图之间的差异，以揭示治疗机制 构成第 4 层结果的阻力。我们将与私营部门合作伙伴合作评估和采用 提高分析能力和速度并降低成本的下一代技术。行政部门 该部门将促进 OMS Atlas 内活动的协调、操作、互动和评估 OMS Atlas 科学家和 HTAN 之间的合作。