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: 10005901
• 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/10005901
• 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; 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; 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; multiple data types; 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; tumor-immune system interactions

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OMIC和多维空间（OMS）地图集，以发现 在转移性乳腺癌和前列腺癌患者中产生的抗药性机制 用当前一代的靶向治疗组合和免疫检查点抑制剂进行治疗。这 OMS地图集的动机是因为这些治疗通常仅在转移性方面有效 环境。可能的抗性机制可能是肿瘤细胞固有的，或源自多样的 肿瘤细胞生活的微环境。 OMS地图集将重点阐明这些抵抗力 在三个特定当前一代临床方案中的机制：（a）激素受体阳性乳腺癌 （HRBC）用CDK4/6抑制剂与内分泌治疗结合治疗，（b）三重阴性 接受PARP抑制剂和免疫调节剂治疗的乳腺癌（TNBC），（C） castation抗性前列腺癌（CRPC）接受恩扎拉胺治疗。我们将实现这一目标 通过在四个领域的工作。生物循环单元将前瞻性地收集，管理和分发纵向 来自来自两个转移性乳腺癌队列中每个患者的20例患者的临床信息，血液和活检和活检 将分析一个前列腺癌队列，以创建三个OMS地图集。活检将保存到 使用多种表征方式启用分析。表征单元将分析（a）OCT冷冻 使用地形单细胞测序（TSC）和单细胞组合索引ATAC-的标本 SEQ（SCI-ATAC-SEQ）以阐明单个细胞中的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）固定的福尔马林固定，石蜡嵌入（FFPE）标本 评估免疫微环境和循环免疫荧光（CYCIF）以评估组成和 肿瘤细胞及其微环境的分子态，以及（c）固定的多聚甲醛树脂嵌入 （PFRE）使用聚焦离子束扫描电子显微镜（FIB-SEM）标本来识别 2D图像中的超微结构变化和具有4 nm分辨率的靶向3D图像。奥马克的特征 SMMART计划将提供相同的肿瘤样品。数据分析单元将开发和部署 （a）管理，分析和可视化的工具，包括原始序列数据和图像的数据 单峰级2结果，（b）通过横向映射整合了omics和成像数据以创建单个 时间点肿瘤图和量化肿瘤细胞亚群的生物学功能，以产生层 3结果，（c）探索术前和/上/治疗后肿瘤图之间的差异，以揭示机制 构成第4层结果的电阻。我们将与私营部门合作伙伴合作评估和采用 下一代技术可以提高分析能力和速度并降低成本。行政 单位将促进OMS Atlas和 在OMS Atlas科学家和HTAN之间。