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