Impact of molecular phenotype on glioma metabolism and growth

分子表型对神经胶质瘤代谢和生长的影响

• 批准号: 8640895
• 负责人: SARAH J. NELSON
• 金额: $ 29.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8640895
• 关键词: 19q; Apoptosis; Appearance; Astrocytoma; Biological Assay; Biopsy; Brain; Brain Neoplasms; Brain region; Cell Density; Cellularity; Characteristics; Chromosome Deletion; Classification; Clinical Management; Creatine; Data; Diffusion; Diffusion weighted imaging; Disease; EGFR gene; Epidermal Growth Factor Receptor; Equilibrium; Genetic Markers; Glioma; Grant; Growth; Histologic; Histology; Histopathologic Grade; Immunohistochemistry; Infiltration; Location; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant Glioma; Metabolic; Metabolism; Molecular; Molecular Genetics; Molecular Profiling; Monitor; N-acetylaspartate; Neurons; Newly Diagnosed; Oligodendroglial Neoplasm; Pathologic; Patients; Pattern; Phosphocreatine; Production; Recurrence; Subgroup; TP53 gene; Therapeutic Intervention; Time; Tissues; Weight; c-erbB-1 Proto-Oncogenes; improved; in vivo; killings; molecular marker; molecular phenotype; neoplastic cell; neuroimaging; oligodendroglioma; outcome forecast; overexpression; prognostic; protein expression; public health relevance; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Patients with non-enhancing malignant gliomas are typically young and may survive 2-10 years before succumbing to their disease. Co-deletion of chromosomes 1p and 19q (1p-19q-) is a marker of chemosensitivity in oligodendroglioma (OD) and mixed oligoastrocytoma (OA). P53 immunopositivity (p53+) is readily observed in Grade 4 astrocytomas that have progressed from lower grades. Amplification of the epidermal growth factor receptor (EGFR+) gene is a marker of poor prognosis irrespective of histologic subtype. Despite the existence of these prognostic molecular markers, clinical management of patients with these tumors remains difficult and the disease is ultimately fatal. Thus, understanding the mechanisms - downstream from molecular alterations - that govern the balance between proliferation and invasion in these tumors is of critical importance for effective longitudinal monitoring and therapeutic intervention.In this project, we will use MRS, high angular diffusion-weighted imaging (HARDI), and histology to investigate the hypotheses that: (1) tCre is positively associated with ADC in 1p19q co-deleted OD/OA, and that tumor cells co-exist with normal neurons (ie non-disruptive infiltration), (2) NAA is positively associated with directional diffusivity in p53+ AS, and histologic examination of tissue biopsies will reveal only a small proportion or no normal intact neurons within the tumor (ie disruptive infiltration), and (3) the combination of MRS and HARDI data, when considered in conjunction with the molecular subtype, can be used to predict the time course and/or peritumoral location of malignant progression. We will (1) compare the metabolic profile and infiltration pattern of non-enhancing oligodendroglial tumors with and without co-deletion of chromosomes 1p and 19q, (2) compare the metabolic profile and infiltration pattern of non-enhancing astrocytoma with differential expression of p53 and EGFR, and (3) Compare the metabolic and diffusion parameters of non-enhancing glioma with time to progression. Understanding the metabolism and infiltration pattern of molecular subtypes of glioma will help to identify synergistic targets for therapy and improve the interpretation of neuroimaging data from patients with these tumors.

描述（由申请人提供）：非增强型恶性胶质瘤患者通常年轻，在死于疾病之前可能存活2-10年。染色体1 p和19 q的共缺失（1 p-19 q-）是少突胶质细胞瘤（OD）和混合性少突星形细胞瘤（OA）化疗敏感性的标志。P53免疫阳性（p53+）在4级星形细胞瘤中很容易观察到，这些星形细胞瘤是从较低级别发展而来的。表皮生长因子受体（EGFR+）基因扩增是预后不良的标志，与组织学亚型无关。尽管存在这些预后分子标志物，但这些肿瘤患者的临床管理仍然困难，并且该疾病最终是致命的。因此，了解这些肿瘤中控制增殖和侵袭之间平衡的分子改变下游机制对于有效的纵向监测和治疗干预至关重要。在本项目中，我们将使用MRS，高角扩散加权成像（HARDI）和组织学来研究以下假设：（1）在1 p19 q共缺失OD/OA中，肿瘤细胞与正常神经元共存时，tCre与ADC呈正相关（2）NAA与p53+ AS的定向扩散率呈正相关，并且组织活检的组织学检查将仅揭示肿瘤内的小部分或没有正常的完整神经元（即破坏性浸润），和（3）MRS和HARDI数据的组合，当与分子亚型结合考虑时，可用于预测恶性进展的时间进程和/或肿瘤周围位置。我们将（1）比较染色体1 p和19 q共缺失和未缺失的非增强型少突胶质细胞瘤的代谢谱和浸润模式，（2）比较p53和EGFR表达差异的非增强型星形细胞瘤的代谢谱和浸润模式，（3）比较非增强型胶质瘤的代谢和扩散参数与进展时间。了解胶质瘤分子亚型的代谢和浸润模式将有助于确定治疗的协同靶点，并改善对这些肿瘤患者神经影像学数据的解释。