Development of Novel Mouse Models to Study REST Function in Medulloblastoma

开发新的小鼠模型来研究髓母细胞瘤的 REST 功能

• 批准号: 8329602
• 负责人: Vidya Gopalakrishnan
• 金额: $ 7.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329602
• 关键词: Accounting; Adverse effects; Biological Models; Biology; Brain; Categories; Cells; Cerebellum; Childhood Brain Neoplasm; Clinical assessments; Complex; Cytoplasmic Granules; Defect; Desmoplastic; Development; Disease; Disease Progression; Dissection; Erinaceidae; Etiology; Evaluation; Event; Exhibits; Face; Failure; Foundations; Functional disorder; Future; Gene Expression; Genetic; Genomic Instability; Goals; Histology; Human; Incidence; Injection of therapeutic agent; Learning Disabilities; M cell; Maintenance; Malignant - descriptor; Mediating; Medicine; Modality; Modeling; Molecular; Movement; Mus; Neoplastic Cell Transformation; Neuronal Differentiation; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Phenotype; Process; Quality of life; RE1-silencing transcription factor; Radiation; Recurrence; Research; Research Personnel; Role; Spinal; Stem cells; Survival Rate; Survivors; Testing; Therapeutic; Toxic effect; Transcription Repressor/Corepressor; Transgenes; Treatment Protocols; Tumor Biology; Work; Xenograft Model; chemotherapy; granule cell; high risk; improved; inhibitor/antagonist; innovation; medulloblastoma; medulloblastoma cell line; mouse model; neoplastic; neoplastic cell; nerve stem cell; neurogenesis; new therapeutic target; novel; outcome forecast; postnatal; pre-clinical; prevent; progenitor; prognostic; small molecule; smoothened signaling pathway; social; tool; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant pediatric brain tumor. Current treatments for this disease include surgery, cranio-spinal radiation and chemotherapy. While this treatment regimen has improved survival rates, survivors face a high risk of recurrence and significant long-term quality of life issues such as uncoordinated movement, learning disabilities and social dysfunction. These side effects result from a failure of the current treatment approaches to target the tumor cells and spare the developing normal brain of young patients. Thus, a more targeted approach to treatment is necessary. However, this requires the identification of disease-specific molecular features. A subset of medulloblastomas is thought to arise from developmental defects in proliferation and neuronal differentiation of the cerebellar granule progenitor cells. The RE1 Silencing Transcription Factor (REST) is a repressor of neurogenesis. REST expression is aberrantly elevated in human medulloblastomas. This abnormal expression of REST is associated with poor prognostic significance for patients with tumors of al histological subtypes. Previous studies have shown patients with anaplastic and desmoplastic histology to have the worst and best outcomes respectively, while patients with classic histology have intermediate outcome. Unexpectedly, patients with desmoplastic tumors that exhibited REST expression have the worst outcome. These findings suggest that REST expression may contribute to tumor progression and cause a more aggressive tumor phenotype. In mice, injection of Myc-immortalized granule cell progenitors constitutively expressing REST transgene promoted tumor formation in the cerebellum. However, neither REST nor Myc alone was sufficient for tumor formation in our studies. These findings also indicate that REST may contribute to tumor progression. Interestingly, REST expression caused genetic instability, raising the possibility that REST may have a role in tumor initiation. REST knockdown in human medulloblastoma cell lines abrogated tumor formation in murine xenograft models, suggesting that REST is required for tumor maintenance. Nevertheless, a careful assessment of the temporal requirement for REST in the tumorigenic process has been hampered by the lack of appropriate mouse models. An important goal of this application is to develop a novel genetically altered mouse model in which REST expression can be conditionally elevated in the granule progenitor cells to determine if it contributes to tumor initiating events such as hyperproliferation, genetic instability and failure of neuronal differentiation. The contribution of REST to disease progression in desmoplastic tumors will also be evaluated in mouse orthotopic models. This work will provide a better understanding of REST biology in tumors and pave the way for development of REST as a novel therapeutic target for medulloblastoma.

描述（由申请人提供）： 髓母细胞瘤是小儿最常见的恶性脑肿瘤。目前对这种疾病的治疗包括手术，颅脊髓放射和化疗。虽然这种治疗方案提高了生存率，但幸存者面临复发的高风险和严重的长期生活质量问题，如运动不协调，学习障碍和社会功能障碍。这些副作用是由于目前的治疗方法未能靶向肿瘤细胞并使年轻患者的正常大脑发育正常。因此，有必要采取更有针对性的治疗方法。然而，这需要鉴定疾病特异性分子特征。髓母细胞瘤的一个亚群被认为是由小脑颗粒祖细胞增殖和神经元分化的发育缺陷引起的。RE1沉默转录因子（REST）是神经发生的阻遏物。人髓母细胞瘤中REST表达异常升高。REST的这种异常表达与所有组织学亚型肿瘤患者的预后不良相关。先前的研究表明，间变性和促结缔组织增生组织学患者的结局分别最差和最好，而经典组织学患者的结局居中。出乎意料的是，表现出REST表达的促结缔组织增生性肿瘤患者的结局最差。这些发现表明REST表达可能有助于肿瘤进展并导致更具侵袭性的肿瘤表型。在小鼠中，注射Myc永生化颗粒祖细胞组成型表达REST转基因促进小脑肿瘤形成。然而，在我们的研究中，REST或Myc单独都不足以形成肿瘤。这些发现还表明，REST可能有助于肿瘤进展。有趣的是，REST表达导致遗传不稳定性，提高了REST可能在肿瘤发生中发挥作用的可能性。在人髓母细胞瘤细胞系中的REST敲低消除了小鼠异种移植模型中的肿瘤形成，表明REST是肿瘤维持所必需的。然而，由于缺乏合适的小鼠模型，对肿瘤发生过程中REST的时间要求进行仔细评估受到阻碍。本申请的一个重要目标是开发一种新的遗传改变的小鼠模型，其中REST表达可以在颗粒祖细胞中有条件地升高，以确定它是否有助于肿瘤起始事件，如过度增殖、遗传不稳定性和神经元分化失败。还将在小鼠原位模型中评价REST对促结缔组织增生性肿瘤疾病进展的贡献。这项工作将提供一个更好的理解REST生物学在肿瘤中，并铺平了道路REST作为一种新的治疗靶点髓母细胞瘤的发展。

项目成果

REST is a novel prognostic factor and therapeutic target for medulloblastoma.

• DOI: 10.1158/1535-7163.mct-11-0990
• 发表时间: 2012-08
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Taylor P;Fangusaro J;Rajaram V;Goldman S;Helenowski IB;MacDonald T;Hasselblatt M;Riedemann L;Laureano A;Cooper L;Gopalakrishnan V
• 通讯作者: Gopalakrishnan V