Molecular Mechanisms and Therapeutic Approaches to Malignant Gliomas

恶性胶质瘤的分子机制和治疗方法

• 批准号: 9187795
• 负责人: INDER Mohan VERMA
• 金额: $ 67.16万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187795
• 关键词: Adult; Affect; Age; American; Astrocytes; Blood Vessels; Brain; Brain Neoplasms; Cells; Cessation of life; Characteristics; DNA Sequence Alteration; Development; Diagnosis; Disease; Endothelial Cells; Etiology; Event; Exhibits; Functional disorder; Genomics; Glioblastoma; Glioma; Growth; Human; I-kappa B Proteins; In Vitro; Intracranial Neoplasms; Laboratories; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Modality; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Neurons; Oncogenic; Operative Surgical Procedures; Pathologic; Pathway interactions; Patients; Phenocopy; Pre-Clinical Model; Primary Brain Neoplasms; Process; Radiation therapy; Recurrence; Recurrent tumor; Resistance; Role; Signal Transduction; Surgeon; System; Testing; Therapeutic; Time; Tissues; Tumor Cell Invasion; United States; angiogenesis; assault; brain tissue; chemotherapy; design; experimental study; genetic profiling; human disease; hypoxia inducible factor 1; improved; mortality; mouse model; neoplastic cell; nerve stem cell; new therapeutic target; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; public health relevance; standard of care; temozolomide; transdifferentiation; treatment effect; tumor; tumor growth

 DESCRIPTION (provided by applicant): Over 22,500 Americans will be diagnosed with brain tumors, and most of them will succumb to the disease. Our laboratory has discovered that gliomas originate by reprogramming of terminally differentiated astrocytes, neurons, and neural stem cells (NSCs) following oncogenic insult. This observation will explain why even after very successful surgery, where the surgeon has removed the majority of the cancer tissue, the tumors recur frequently. Additionally the tumors can transdifferentiate into functional blood vessels, thus thwarting the traditional anti-angiogenic therapies. The Verma laboratory seeks to understand the molecular mechanisms of dedifferentiation, trans-differentiation, and will undertake possible therapeutic approaches. Aim 1: Phenocopying human glioblastoma multiforme (GBM) in a mouse model for therapeutic treatment. The Verma laboratory plans to phenocopy the radiotherapy and chemotherapy (temozolomide) treatments that patients undergo following GBM diagnosis in our lentiviral induced GBM system. The aim is to mimic this situation and evaluate the effect of these treatments on tumor growth and invasion. Aim 2: Mechanisms of tumor cell trans-differentiation to endothelial cells: Trans-differentiation of gliom cells to endothelial cells (TDECs) was a major surprise and reflects the plasticity of tumor cells. To understand molecular mechanisms involved in their formation and delineation of their specific characteristics, detailed genetic profiling of mouse and human TDECs will be carried out. Specifically the role of Sema3e and HIF-1 in tumor development and TDEC formation will be determined. Aim 3: Novel therapeutic approaches for GBM Treatment: Since the GBM mouse models generally recapitulate the pathologic and molecular hallmarks of the human disease, the Verma laboratory proposes to take advantage of the preclinical mouse GBM model to test novel therapeutic approaches targeting: (a) angiogenesis including TDEC angiogenesis, and anti-angiogenic therapy-induced hyperinvasiveness, and (b) the NFkB pathway, which we have found to be constitutively activated in GBM tumors. This laboratory has generated a unique model of mouse gliomas that can serve as a preclinical model for a variety of mechanistic and therapeutic modalities being developed in the Verma laboratory.

 描述（申请人提供）：超过22，500名美国人将被诊断患有脑肿瘤，其中大多数人将死于这种疾病。我们的实验室已经发现，胶质瘤起源于终末分化的星形胶质细胞，神经元和神经干细胞（NSC）在致癌损伤后的重编程。这一观察结果将解释为什么即使在非常成功的手术后，外科医生已经切除了大部分癌组织，肿瘤也会频繁复发。此外，肿瘤可以转分化为功能性血管，从而阻碍了传统的抗血管生成疗法。Verma实验室试图了解去分化、转分化的分子机制，并将采取可能的治疗方法。目的1：在小鼠模型中复制人多形性胶质母细胞瘤（GBM）用于治疗性治疗。Verma实验室计划在我们的慢病毒诱导GBM系统中对患者在GBM诊断后接受的放疗和化疗（替莫唑胺）治疗进行表型复制。目的是模拟这种情况，并评估这些治疗对肿瘤生长和侵袭的影响。目标二：肿瘤细胞转分化为内皮细胞的机制：胶质细胞转分化为内皮细胞（TDEC）是一个重大的惊喜，反映了肿瘤细胞的可塑性。 为了了解其形成的分子机制和其具体特征的描述，将对小鼠和人类TDEC进行详细的遗传分析。具体地，将确定Sema 3e和HIF-1在肿瘤发展和TDEC形成中的作用。目标3：GBM治疗的新治疗方法：由于GBM小鼠模型通常概括了人类疾病的病理和分子特征，Verma实验室建议利用临床前小鼠GBM模型来测试新的治疗方法，靶向：（a）血管生成，包括TDEC血管生成，和抗血管生成治疗诱导的超侵袭性，和（B）NFkB途径，我们发现它在GBM肿瘤中被组成性激活。该实验室已经产生了一种独特的小鼠胶质瘤模型，可以作为Verma实验室正在开发的各种机制和治疗方式的临床前模型。