NEUROPATHOLOGY/TISSUE BANK CORE

神经病理学/组织库核心

基本信息

批准号：
10706502
负责人：
Claudia Katharina Petritsch
金额：
$ 12.42万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706502
关键词：
3-Dimensional ATAC-seq Address Adherent Culture Archives Area Blood Vessels Brain Breast Cancer Patient Cell Line Cells Cerebrospinal Fluid Clinical Clinical Trials Clonal Evolution Collaborations Collection Complement Consent Data Development Disease Dissociation Distant Excision Exhibits Frequencies Fresh Tissue Gene Expression Profile Genomics Grant Growth Heterogeneity Image Immune Immune checkpoint inhibitor Immune system Immunosuppression Immunotherapy In Vitro Infiltration Institution Interruption Intracarotid Length Lung Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of gastrointestinal tract Metastatic malignant neoplasm to brain Microglia Modeling Molecular Molecular Profiling Morbidity - disease rate Mutation Myeloid-derived suppressor cells Neoplasm Metastasis Neuroglia Neuroimmune Neurosphere Office of Administrative Management Operative Surgical Procedures Pathway interactions Patients Pre-Clinical Model Preclinical Testing Primary Neoplasm Prognostic Marker Proliferating Quality Control Radiation Radiation therapy Radiology Specialty Research Research Personnel Resistance Resources Risk Role Sampling Serum Signal Pathway Signal Transduction Solid Solid Neoplasm Specimen Stress T cell infiltration T-Lymphocyte Tissue Banks Tissue Microarray Tissues Transforming Growth Factor beta Tumor-associated macrophages Work Xenograft Model Xenograft procedure blood-brain barrier permeabilization brain surgery cancer biomarkers cancer type cell type checkpoint inhibition clinically relevant data management genome sequencing immunotherapy clinical trials improved in vitro Model in vivo in vivo Model insight melanoma metastatic process model development molecular targeted therapies monocyte mortality mouse model multidisciplinary nano-string neoplastic cell neuropathology next generation sequencing peripheral blood predictive marker prognostic radiation response repository response single-cell RNA sequencing small molecule inhibitor stemness tissue archive tissue fixing tool treatment and outcome

项目摘要

ABSTRACT – NEUROPATHOLOGY CORE Surgical resection and/or radiotherapy effectively reduce the growth of brain metastases (BMs) in many patients. However, after initial responses, BMs frequently acquire resistance to radiation and exhibit local and distant progression which significantly contributes to the morbidity and mortality of cancer patients. Early clinical results for targeting BMs by immunotherapies, including immune checkpoint inhibition (ICI), are encouraging and indicate that combination of radiation and immunotherapies will be very beneficial to BMs patients. Currently, it is not feasible to identify patients at risk to develop BMs prior to radiologic or clinical manifestation and to determine responses to radiation and immunotherapies. BMs are clonally distinct from the primary cancer intrinsically heterogeneous, which provides a challenge for effectively treating BMs. It is therefore critical to identify predictive and prognostic BM biomarkers for cancer patients. We propose two aims to address these unmet need in patients with solid cancers. In Aim 1. we will generate a repository for matched primary cancer- brain metastases specimens for clinicopathologic and molecular correlations to support Projects 1, 2 and 3. We will integrate patient-material collection into the Projects by providing regulatory oversight, quality control, processing, storage, and tracking of archived material. Matched primary cancer-BMs specimens from different solid cancers types will be analyzed for clinicopathologic and molecular correlations using tissue microarrays (TMAs) and the nanoString nCounter platform. Collectively, Aim 1-related research is expected to yield predictive biomarkers and prognostic biomarkers for rational integration of multidisciplinary treatments. In Aim 2. we propose to centrally generate and validate clinically relevant, experimental syngeneic and xenogeneic BM models to catalyze Projects 1, 2 and 3-related research. We will leverage the available fresh tissue collected from cancer and BM surgeries to generate tools for all Projects, including single-cell resources and in vitro (2D/3D-neurosphere) and in vivo BM models. Dr. Petritsch, who is heading a patient-derived modeling team, will lead the Neuropathology Core. Dr. Vogel, who is the Director of Neuropathology, will be a Co-Investigator. The Core will therefore leverage significant institutional resources already in place to support the U54, and the clinical trials that we expect to result from this proposed work. The Core will centrally annotate the attached clinical, treatment and outcomes data for all collected BMs specimens, which include FFPE tissue, TMAs, fresh tissue and validated 2D/3D and in vivo model-derived resources. The Neuropathology Core will closely interact with the Administrative and Data Management and Toolkit Cores. By integrating clinicopathologic studies with in vitro and in vivo modeling of the brain metastatic process, the Neuropathology Core will catalyze BM research for the entire length of the grant. 1

摘要 - 神经病理学核心手术切除和/或放射疗法有效地减少了许多患者的脑转移（BMS）的生长。但是，经过初始响应后，BMS经常获得对辐射的抵抗力，并暴露于局部和远处进展显着导致癌症患者的发病率和死亡率。早期临床结果用于通过包括免疫抑制（ICI）在内的免疫疗法来靶向BM，这是令人鼓舞的，并且表明辐射和免疫疗法的组合对BMS患者非常有益。目前，它在放射学或临床表现之前识别有风险的患者不可行确定对辐射和免疫疗法的反应。 BMS与原发性癌症不同本质上异质，这为有效治疗BMS提供了挑战。因此，至关重要确定癌症患者的预测性和预后BM生物标志物。我们提出了两个目的来解决这些固体癌症患者的需求未满足。在AIM 1中。我们将生成一个用于匹配的原发性癌症的存储库 - 用于支持项目1、2和3的临床病理学和分子相关性的脑转移标本。通过提供监管，质量控制，存档材料的处理，存储和跟踪。匹配来自不同的原发性癌症-BMS标本将使用组织微阵列分析固体癌症类型的临床病理学和分子相关性（TMA）和Nanostring ncounter平台。总体而言，AIM 1相关研究将产生预测性生物标志物和预后生物标志物，用于合理的多学科治疗。在目标2.我们提议集中生成和验证临床相关，实验性合法性和异种BM 催化项目1、2和3相关研究的模型。我们将利用可用的新鲜组织从癌症和BM手术到为所有项目生成工具，包括单细胞资源和体外（2D/3D-NEUROPHERE）和体内BM模型。佩特里奇（Petritsch）博士将领导一支患者衍生的建模团队，将领导神经病理学核心。神经病理学主任Vogel博士将成为共同研究者。这因此，核心将利用已经有大量的机构资源来支持U54和临床我们期望由这项拟议的工作产生的试验。核心将集中注释所附的临床，所有收集的BMS标本的治疗和结果数据，其中包括FFPE组织，TMA，新鲜组织并验证了2D/3D和体内模型衍生的资源。神经病理学核心将与行政和数据管理以及工具包内核。通过将临床病理学研究与体外整合脑转移过程的体内建模，神经病理学核心将催化BM研究赠款的整个长度。 1