Bidirectional interaction of platelets and tumor cells in patients with glioblastoma

胶质母细胞瘤患者血小板与肿瘤细胞的双向相互作用

• 批准号: 10684771
• 负责人: KRISHNA PL BHAT
• 金额: $ 56.05万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-05 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684771
• 关键词: Address; Adult; Antibodies; Beds; Biological Assay; Biological Markers; Biopsy; Blocking Antibodies; Blood; Blood Platelets; Bone Marrow; Brain Neoplasms; Brain imaging; C-Type Lectins; Cancer Patient; Circulation; Clinical; Dangerousness; Data; Diagnosis; Disease; Disease Progression; Early Diagnosis; Evolution; Excision; Gene Expression Profile; Glioblastoma; Glioma; Goals; Growth; Heterogeneity; Human; IL6 gene; Image; Individual; Inflammatory; Interleukin-6; Intracranial Neoplasms; Knowledge; Ligands; Magnetic Resonance; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Megakaryocytes; Membrane Proteins; Messenger RNA; Molecular; Molecular Analysis; Monitor; Mus; Mutation; Neoplasm Circulating Cells; Outcome; Patients; Persons; Plasma; Platelet Count measurement; Platelet aggregation; Prediction of Response to Therapy; Production; RNA; Recurrence; Recurrent tumor; Reporting; Role; Sampling; Serum; Signal Transduction; Technology; Testing; Thrombus; Time; Tissues; Transfer RNA; Translating; Tumor Biology; Tumor Burden; Tumor Tissue; Tumor-Derived; United States; Unresectable; Work; Xenograft procedure; blood-based biomarker; burden of illness; cancer cell; cell free DNA; chemoradiation; clinical diagnostics; cohort; cytokine; epidermal growth factor receptor VIII; extracellular vesicles; improved; liquid biopsy; molecular subtypes; neoplastic cell; outcome prediction; podoplanin; predicting response; prognostic; prospective; receptor; response; stem-like cell; therapy resistant; thrombocytosis; treatment response; tumor; tumor microenvironment; tumor progression

PROJECT SUMMARY Glioblastoma is among the most lethal of all cancers and the most common primary malignant brain tumor, typically lethal by 15 months. After initial tumor resection, we rely on an imperfect measure of disease response, namely magnetic resonance brain imaging, as obtaining tumor tissue at recurrence is often dangerous or fails to impact survival and is rarely performed. Indeed, many patients rely only on a tiny biopsy for initial diagnosis with no ability for subsequent deep molecular analyses, let alone monitoring of disease over time. The current proposal will address a fundamental gap in the field of GBM, i.e. the lack of predictors not dependent on the availability of tumor tissue and those that can provide real-time, tissue-free tumor monitoring, which is particularly critical in monitoring treatment response and assessing disease progression longitudinally. Blood-based biomarkers such as circulating tumor cells and cell free DNA are attractive, but have yet to provide meaningful results in GBM (compared to other cancers) and have yet to become clinical diagnostics. Tumor educated platelets (TEPs) has recently been reported and shown to contain tumor-specific gene expression signatures that are associated with outcome for several tumor types, but the clinical value and the mechanisms of enrichment of TEPs are unknown. The overall goals of this proposal are to elucidate the mechanism underlying the tumor cell–platelet interaction that leads to TEPs and to develop a TEP-based liquid biopsy platform for longitudinal monitoring of disease in patients with GBM. In this project, we will test the hypothesis that platelet numbers are increased in response to tumor signaling in the bone marrow and that platelets take up tumor- derived extracellular vesicles containing RNA cargo in a PDPN dependent manner. TEP RNA signatures reflect underlying tumor biology, growth, and treatment resistance, and will be utilized as biomarkers. In Aim 1, we will test the hypothesis that pro-inflammatory cytokine-mediated paraneoplastic thrombocytosis promotes formation of TEP signatures in GBM. In Aim 2, we will test the hypothesis that PDPN interaction with the CLEC2 receptor contributes to transfer of RNA from tumor cells to platelets. In Aim 3, we will test the hypothesis that TEP RNA signatures can be used to monitor disease burden longitudinally in patients with GBM.

项目摘要 胶质母细胞瘤是所有癌症中最致命的，也是最常见的原发性恶性脑肿瘤， 一般15个月就致命在最初的肿瘤切除后，我们依赖于不完美的疾病反应衡量标准， 即磁共振脑成像，因为在复发时获得肿瘤组织通常是危险的，或者不能 影响生存，很少执行。事实上，许多患者仅依靠微小的活检进行初步诊断， 没有能力进行后续的深入分子分析，更不用说随着时间的推移监测疾病了。当前 该提案将解决GBM领域的一个根本空白，即缺乏不依赖于 肿瘤组织的可用性和那些可以提供实时，无组织肿瘤监测，特别是 在监测治疗反应和纵向评估疾病进展方面至关重要。基于血液 生物标志物如循环肿瘤细胞和无细胞DNA是有吸引力的，但尚未提供有意义的生物标志物。 导致GBM（与其他癌症相比），尚未成为临床诊断。肿瘤教育 血小板（TEPs）最近被报道并显示含有肿瘤特异性基因表达特征 与几种肿瘤类型的结果相关，但其临床价值和机制 TEPs的富集是未知的。本提案的总体目标是阐明 肿瘤细胞-血小板相互作用导致TEPs，并开发基于TEPs的液体活检平台， GBM患者疾病的纵向监测。在这个项目中，我们将测试假设， 数量增加是对骨髓中肿瘤信号的反应，血小板吸收肿瘤， 以PDPN依赖性方式含有RNA货物的衍生的细胞外囊泡。TEP RNA标签反映了 潜在的肿瘤生物学、生长和治疗抗性，并将用作生物标志物。 在目标1中，我们将检验促炎性丝氨酸介导的副肿瘤性细胞因子表达的假设。 血小板增多促进GBM中TEP标记的形成。在目标2中，我们将检验PDPN 与CLEC 2受体的相互作用有助于RNA从肿瘤细胞转移到血小板。在目标3中，我们 检验TEP RNA特征可用于纵向监测患者疾病负担的假设 关于GBM