NEUROPATHOLOGY/TISSUE BANK CORE

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(BMS)的生长。 然而，在最初的反应之后，BMS经常获得对辐射的抵抗力，并表现出局部和远程 癌症的进展对癌症患者的发病率和死亡率有很大的影响。早期临床结果 通过免疫疗法，包括免疫检查点抑制(ICI)来靶向BMS，是令人鼓舞的， 提示放射治疗与免疫治疗相结合对BMS患者有很大益处。目前，它 在放射或临床表现之前识别有患BMS风险的患者并不可行 确定对放射和免疫疗法的反应。骨髓增生异常综合征在克隆性方面不同于原发癌症。 本质上的异质性，这为有效治疗BMS提供了挑战。因此，至关重要的是 为癌症患者确定预测和预后的骨髓生物标记物。我们提出了两个目标来解决这些问题 实体癌症患者未得到满足的需求。在目标1中，我们将为匹配的原发癌症生成一个储存库- 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。 将通过提供监管监督、质量控制、 对存档材料进行处理、存储和跟踪。来自不同来源的匹配的原发癌-BMS标本 将使用组织微阵列分析实体癌类型的临床病理和分子相关性 (TMAS)和纳米串计数器平台。总的来说，与AIM 1相关的研究有望产生预测性 合理整合多学科治疗的生物标志物和预后生物标志物。在目标2中，我们 建议集中生成和验证临床相关的实验性同基因和异种骨髓 促进项目1、2和3相关研究的模型。我们将利用收集到的可用的新鲜组织 从癌症和骨髓手术到为所有项目生成工具，包括单细胞资源和体外 (2D/3D-Neuroball)和活体骨髓模型。佩特里奇博士领导着一个由患者衍生的建模团队，他将 领导神经病理核心。沃格尔博士是神经病理学主任，将担任联合调查员。这个 因此，CORE将利用现有的大量机构资源来支持U54和临床 我们预计这项拟议的工作将导致试验。核心将集中注释所附的临床， 所有收集的BMS样本的治疗和结果数据，包括FFPE组织、TMA、新鲜组织 并验证了2D/3D和体内模型派生的资源。神经病理核心将与 管理、数据管理和工具包核心。通过将临床病理研究与体外研究相结合 和脑转移过程的活体建模，神经病理学核心将催化BM研究 整个资助金期限。 1

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