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

• 批准号: 9899209
• 负责人: Joanna Phillips
• 金额: $ 36.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/9899209
• 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; Xenograft procedure; 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 population; patient stratification; phosphoproteomics; precision medicine; predictive marker; preservation; prognostic; prognostic significance; response; response biomarker; sample fixation; spectroscopic imaging; success; targeted treatment; tumor; tumor heterogeneity; tumor metabolism

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).

项目概要 弥漫性胶质瘤，包括少突胶质细胞瘤、星形细胞瘤和高度恶性的胶质母细胞瘤（GBM） 最常见的原发性恶性脑肿瘤类型。磷脂酰肌醇 3 的活化增加 (PI3)-激酶/AKT/mTOR 信号通路在 GBM 中很常见，似乎是 GBM 的一种机制 肿瘤从低级别弥漫性神经胶质瘤恶变为GBM。鉴于此的重要性 疾病途径中，几种针对该途径的治疗策略正在早期临床试验中进行测试。到 最大限度地提高这些疗法的益处并最大限度地减少毒性，但是，为患者提供准确而强大的生物标志物 需要对疾病对治疗的反应进行分层和评估。蛋白质磷酸化分析 提供有关信号通路活动的综合功能信息。该提案的目标是使用 生物样本科学，用于识别和减轻分析前因素，包括肿瘤内异质性， 组织采集和混淆非肿瘤细胞，可能会掩盖蛋白质的准确分析 弥漫性神经胶质瘤中的磷酸化。我们假设准确的评估需要小型且保存完好的 和生物靶向肿瘤活检。为了研究这个假设，我们提出了一个多学科团队 具有多次图像引导活检、脑肿瘤采集和分析专业知识的研究人员 生物学、生物样本库、神经病理学、成像、生物统计学和神经肿瘤学。首先，我们调查 使用术前将肿瘤活检靶向生物侵袭性肿瘤区域的创新方法 使用基于 5-氨基乙酰丙酸 (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检测方法和最先进的单细胞质谱流式细胞术来评估 PI3K/AKT/mTOR 信号通路活性并确定非肿瘤细胞对整体的贡献 磷蛋白水平。第三，利用我们开发的循证方法和途径，我们将 研究蛋白质确定的 PI3K/AKT/mTOR 信号通路活性的预后意义 通过与我们的 Phase 整合，在弥漫性神经胶质瘤和接受 mTOR 抑制剂治疗的患者中进行磷酸化 2 项针对 PI3K/AKT/mTOR 信号通路的临床试验 (NCT02023905)。