Mitigation of preanalytic factors influencing brain tumor protein phosphorylation

减轻影响脑肿瘤蛋白磷酸化的分析前因素

基本信息

批准号：
10369600
负责人：
Joanna Phillips
金额：
$ 36.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369600
关键词：
1-Phosphatidylinositol 3-Kinase Address Adult Affect Aminolevulinic Acid BRAT gene Behavior Biological Biological Assay Biological Markers Biometry Biopsy Brain Neoplasms Cells Clinical Clinical Trials Clinical assessments Cytometry Data Diffuse Disease Epitopes Evaluation Geography Glioblastoma Glioma Goals Image Image Guided Biopsy Institution Ischemia MGMT gene Malignant - descriptor Malignant neoplasm of brain Methodology Methods Methylation Modeling Oligodendroglioma-Astrocytoma Oncogenic PI3K/AKT Pathologic Pathway interactions Patients Performance Phase I Clinical Trials Phase II Clinical Trials Phosphoproteins Phosphorylation Progression-Free Survivals Protein Analysis Proteomics Proto-Oncogene Proteins c-akt Protocols documentation Recurrence Research Personnel S-Phase Fraction Science Sensitivity and Specificity Signal Pathway Signal Transduction Standardization Technology Temperature Testing Therapeutic Time Tissues Toxic effect Tumor Biology Tumor Tissue base biobank clinical practice clinically relevant early phase clinical trial evidence base image guided improved individual patient individual variation innovation mTOR Inhibitor mTOR Signaling Pathway multidisciplinary mutant neuro-oncology neuropathology patient biomarkers patient derived xenograft model patient population patient stratification phosphoproteomics precision medicine predictive marker preservation prognostic prognostic significance response biomarker sample fixation spectroscopic imaging success targeted treatment treatment response tumor tumor heterogeneity tumor metabolism

1-Phosphatidylinositol 3-Kinase Address Adult Affect Aminolevulinic Acid BRAT gene Behavior Biological Biological Assay Biological Markers Biometry Biopsy Brain Neoplasms Cells Clinical Clinical Trials Clinical assessments Cytometry Data Diffuse Disease Epitopes Evaluation Geography Glioblastoma Glioma Goals Image Image Guided Biopsy Institution Ischemia MGMT gene Malignant - descriptor Malignant neoplasm of brain Methodology Methods Methylation Modeling Oligodendroglioma-Astrocytoma Oncogenic PI3K/AKT Pathologic Pathway interactions Patients Performance Phase I Clinical Trials Phase II Clinical Trials Phosphoproteins Phosphorylation Progression-Free Survivals Protein Analysis Proteomics Proto-Oncogene Proteins c-akt Protocols documentation Recurrence Research Personnel S-Phase Fraction Science Sensitivity and Specificity Signal Pathway Signal Transduction Standardization Technology Temperature Testing Therapeutic Time Tissues Toxic effect Tumor Biology Tumor Tissue base biobank clinical practice clinically relevant early phase clinical trial evidence base image guided improved individual patient individual variation innovation mTOR Inhibitor mTOR Signaling Pathway multidisciplinary mutant neuro-oncology neuropathology patient biomarkers patient derived xenograft model patient population patient stratification phosphoproteomics precision medicine predictive marker preservation prognostic prognostic significance response biomarker sample fixation spectroscopic imaging success targeted treatment treatment response tumor tumor heterogeneity tumor metabolism

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项目摘要

PROJECT SUMMARY Diffuse gliomas, including oligodendroglioma, astrocytoma, and the highly malignant glioblastoma (GBM), are the most common type of primary malignant brain tumor. Increased activation of the phosphatidylinositol 3 (PI3)-kinase/AKT/mTOR signaling pathway is common in GBM and appears to be one mechanism of malignant transformation of tumors from lower grade diffuse glioma to GBM. Given the importance of this pathway in disease, several therapeutic strategies that target it are being tested in early phase clinical trials. To maximize benefit and minimize toxicity to these therapies, however, accurate and robust biomarkers for patient stratification and assessment of disease response to therapy are needed. Analysis of protein phosphorylation provides integrated, functional information about signaling pathway activity. The goal of this proposal is to use biospecimen sciences to identify and mitigate the preanalytic factors, including intratumoral heterogeneity, tissue acquisition, and confounding non-neoplastic cells, that can obscure accurate analysis of protein phosphorylation in diffuse glioma. We hypothesize that accurate assessment will require small, well-preserved and biologically targeted tumor biopsies. To investigate this hypothesis we propose a multidisciplinary team of investigators with expertise in the acquisition and analysis of multiple and image-guided biopsies, brain tumor biology, biobanking, neuropathology, imaging, biostatistics, and neuro-oncology. First, we investigate innovative approaches to target tumor biopsies to biologically aggressive tumor regions using pre-operative MR spectroscopic imaging and intra-operative tumor metabolism using 5-aminolevulinic acid (ALA)-based imaging. Second, we use clinically validated assays and state-of-the-art single cell mass cytometry to evaluate PI3K/AKT/mTOR signaling pathway activity and determine the contribution of non-neoplastic cells to overall phosphoprotein levels. Third, using the evidence-based methodologies and approaches we develop, we will investigate the prognostic significance of PI3K/AKT/mTOR signaling pathway activity as determined by protein phosphorylation in diffuse glioma and in patients treated with an mTOR inhibitor by integration with our Phase 2 clinical trial targeting the PI3K/AKT/mTOR signaling pathway (NCT02023905).

项目摘要弥漫性神经胶质瘤，包括少突可瘤，星形胶质细胞瘤和高度恶性胶质母细胞瘤（GBM）是原发性恶性脑肿瘤的最常见类型。磷脂酰肌醇3的激活增加（PI3） - 激酶/AKT/MTOR信号传导途径在GBM中很常见，似乎是一种机制肿瘤从低级弥漫性神经胶质瘤到GBM的恶性转化。考虑到这一点的重要性疾病的途径，在早期临床试验中对目标进行测试的几种治疗策略。到然而需要分层和评估疾病对治疗的反应。蛋白质磷酸化的分析提供有关信号通路活动的集成功能信息。该提议的目的是使用生物循环科学，以识别和减轻肿瘤内异质性，包括肿瘤内的因素组织采集和混淆非肿瘤细胞，可以掩盖对蛋白质的准确分析弥漫性神经胶质瘤中的磷酸化。我们假设准确的评估需要较小的保存良好和生物靶向的肿瘤活检。为了调查这一假设，我们提出了一个多学科团队在获取和分析多重和图像引导活检，脑肿瘤方面具有专业知识的研究者生物学，生物库，神经病理学，成像，生物统计学和神经肿瘤学。首先，我们调查使用术前的创新方法将肿瘤活检靶向生物学上的侵略性肿瘤区域使用基于5-氨基乙酸（ALA）的MR光谱成像和术中肿瘤代谢成像。其次，我们使用经过临床验证的测定法和最先进的单细胞质量细胞仪来评估 PI3K/AKT/MTOR信号通路活动，并确定非塑性细胞对总体的贡献磷蛋白水平。第三，使用我们开发的基于证据的方法和方法，我们将研究蛋白质确定的PI3K/AKT/MTOR信号通路活动的预后意义通过与我们的相结合，弥漫性神经胶质瘤和用MTOR抑制剂治疗的患者的磷酸化 2针对PI3K/AKT/MTOR信号通路（NCT02023905）的临床试验。