NEUROPATHOLOGY/TISSUE BANK CORE

神经病理学/组织库核心

• 批准号: 10272363
• 负责人: Claudia Katharina Petritsch
• 金额: $ 17.13万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10272363
• 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 Treatment; Clinical Trials; Clonal Evolution; Collaborations; Collection; Complement; Consent; Data; Development; Disease; Distant; Excision; Exhibits; Frequencies; Fresh Tissue; Gene Expression Profile; Genomics; Grant; Growth; Heterogeneity; Image; Immune; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunotherapy; In Vitro; Interruption; Intracarotid; Lead; 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; Office of Administrative Management; Operative Surgical Procedures; Pathway interactions; Patients; Pre-Clinical Model; Preclinical Testing; Primary Neoplasm; Prognostic Marker; Quality Control; Radiation; Radiation therapy; Radiology Specialty; Research; Research Personnel; Resistance; Resources; Risk; Role; Sampling; Seeds; Serum; Signal Pathway; Signal Transduction; Solid; Solid Neoplasm; Specimen; Stress; Suggestion; T-Lymphocyte; Tissue Banks; Tissue Microarray; Tissues; Transforming Growth Factor beta; Treatment outcome; Tumor-associated macrophages; Work; Xenograft Model; Xenograft procedure; blood-brain barrier permeabilization; 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; tool

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/或放射治疗有效地减少了许多患者脑转移瘤（BM）的生长。 然而，在最初的反应后，BM经常获得对辐射的抵抗力，并表现出局部和远距离的放射性。 癌症的进展，其显著地导致癌症患者的发病率和死亡率。早期临床结果 通过免疫疗法靶向BM，包括免疫检查点抑制（ICI），是令人鼓舞的， 表明放射和免疫疗法组合将对BM患者非常有益。目前它 在放射学或临床表现之前识别有发生BM风险的患者， 确定对辐射和免疫疗法的反应。BM在克隆上与原发癌不同， 本质上是异质的，这为有效治疗BM提供了挑战。因此， 鉴定癌症患者的预测和预后BM生物标志物。我们提出两个目标来解决这些问题 实体癌患者的未满足需求。在目标1中。我们将为匹配的原发性癌症建立一个储存库 脑转移瘤标本的临床病理和分子相关性，以支持项目1，2和3。我们 将通过提供监管监督、质量控制， 归档材料的处理、存储和跟踪。匹配的原发性癌症-来自不同组织的BM标本 将使用组织微阵列分析实体癌类型的临床病理学和分子相关性 （TMA）和nanoString nCounter平台。总的来说，目标1相关的研究预计将产生预测性的结果。 生物标志物和预后生物标志物，用于多学科治疗的合理整合。在目标2中。我们 建议集中生成并验证临床相关的实验性同基因和异种BM 模型，以促进项目1，2和3相关的研究。我们将利用收集到的新鲜组织 从癌症和骨髓手术中提取的细胞，为所有项目生成工具，包括单细胞资源和体外 (2D/3D-神经球）和体内BM模型。Petritsch博士领导着一个患者衍生模型团队， 领导神经病理学核心Vogel博士是神经病理学主任，将担任合作研究者。的 因此，核心将利用已经到位的重要机构资源来支持U 54和临床 我们希望通过这项拟议工作进行的试验。核心将集中注释随附的临床， 所有采集的BM标本的治疗和结局数据，包括FFPE组织、TMA、新鲜组织 并验证了2D/3D和体内模型衍生资源。神经病理学核心将与 行政和数据管理以及工具包核心。通过整合临床病理学研究和体外 和脑转移过程的体内建模，神经病理学核心将催化BM研究， 整个补助期。 1