Developmental studies to inform clinical stratification and targeting of SHH MB

为 SHH MB 的临床分层和靶向提供信息的发展研究

• 批准号: 9253355
• 负责人: ALEXANDRA L. JOYNER
• 金额: $ 44.98万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-04 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253355
• 关键词: Adult; Affect; Age; Age of Onset; Anatomy; Automobile Driving; Basic Science; Biological; Biology; Birth; CSF1R gene; Candidate Disease Gene; Cell Lineage; Cells; Cerebellar Diseases; Cerebellum; Child; Childhood Malignant Brain Tumor; Clinical; Clinical Data; Clinical stratification; Cognitive deficits; Collaborations; DNA sequencing; Data Set; Development; Diagnosis; Disease; FRAP1 gene; Foundations; GLI2 gene; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic Transcription; Genomic approach; Genomics; Growth; Heterogeneity; Histology; Human; Image; Inherited; Inter-tumoral heterogeneity; Label; Lateral; Lesion; Location; Magnetic Resonance Imaging; Malignant neoplasm of brain; Microglia; Modeling; Molecular; Mosaicism; Mus; Mutant Strains Mice; Mutation; Neurologic; PI3K/AKT; Pathway interactions; Patients; Phenotype; Population; Pre-Clinical Model; Preclinical Testing; Proliferating; Protocols documentation; Quality of life; Radiation therapy; Recurrence; Reproducibility; Resistance development; Role; SHH gene; Sampling; Signal Transduction; Stratification; Subgroup; Survivors; TP53 gene; Techniques; Testing; Time; Tissue Sample; Transplantation; Tumor stage; Tumor-Derived; age group; angiogenesis; apoAI regulatory protein-1; base; cancer genetics; cell type; chemotherapy; cytokine; experimental study; genome-wide analysis; granule cell; improved; inhibitor/antagonist; insight; loss of function mutation; macrophage; man; medulloblastoma; mouse model; mutant; neoplastic cell; new therapeutic target; outcome forecast; postnatal; progenitor; public health relevance; receptor; response; smoothened signaling pathway; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; translational study; tumor; tumor growth; tumor microenvironment; tumor progression; unnecessary treatment

 DESCRIPTION (provided by applicant): Recent genome-wide analyses have changed the diagnosis of medulloblastoma (MB), the most common malignant brain tumor in children. It is now clear that MB is not a single disease of the cerebellum (CB), but encompasses a range of disease subgroups with diverse clinical presentations, histology, and pathway activation, cells of origin and cancer genetics. Given the complexity of MB, development of targeted therapies tailored to each patient will require deeper insight into the major pathways fueling the disease and further subdivision of the current 4 subgroups of patients. The sonic hedgehog (SHH) subgroup represents ~30% of MBs, has intermediate prognosis, and can arise from granule cell precursors (GCPs) that proliferate in response to SHH. The SHH subgroup of MB is diverse at all levels, and each factor is likely to influence prognosis and be critical for treatment. Loss-of function mutations are seen in genes that inhibit SHH signaling (PTCH1), activating mutations in the receptor SMO (e.g. SmoM2) and amplifications of the effector gene GLI2 and its targets associated with loss of TP53. Current HH inhibitors are only effective in a small percentage of MBs, and all patients develop resistance. We hypothesize that some of the intertumoral heterogeneity within SHH-MBs is due to their arising from different cell lineages, at different times, and in different anatomic regions of the CB. Additionally, that cellular and transcriptional states inherited from distinct cells of origin are maintained in the mature tumor, and could represent targets for therapy. Basic research approaches in mouse models are thus necessary as a foundation for translational studies. We have studied the SHH-GLI pathway in mammalian development for 20 years, with a focus on the CB. Recently we developed sporadic MB models with mutations in Ptch1 or Smo. Significantly, reproducible yet distinct histologies are seen during tumor progression in each model. Moreover, the majorities of lesions seen at early stages regresses and have different cellular phenotypes to lesions that progress to MB. We propose to: Aim 1. Marker analysis and longitudinal Mn-Enhanced MRI (Turnbull) of Ptch1 and SmoM2 models initiated at 2 developmental stages and lineages, and identify candidate intrinsic genes that influence progression of SHH-MBs (RNA-seq profiling). Aim 2. Define the microenvironment and test how tumor associated microglia and macrophages influence SHH-MB progression. Aim 3. Determine whether select candidate genes identified in Aims 1/2, mTOR signaling or NR2F2 alter SHH- MB progression and compare the results to human SHH-MB data sets (Taylor) and tumor samples. Our experimental studies of MB progression in mouse models will synergize with human MB studies and should aid in stratification of SHH subgroup patients, wherein new therapies targeted to essential pathways driving MB progression can be tested, improving both prognosis and quality of life for survivors.

 描述（由申请人提供）：最近的全基因组分析改变了髓母细胞瘤（MB）的诊断，这是儿童中最常见的恶性脑肿瘤。现在很清楚，MB不是一种单一的小脑疾病（CB），而是包括一系列具有不同临床表现、组织学和通路激活、起源细胞和癌症遗传学的疾病亚组。鉴于MB的复杂性，开发针对每位患者的靶向治疗将需要更深入地了解助长疾病的主要途径，并进一步细分当前4个亚组的患者。音刺猬（SHH）亚组占MB的约30%，具有中等预后，并且可以由响应SHH而增殖的颗粒细胞前体（GCPs）产生。MB的SHH亚组在所有水平上都是多样的，每个因素都可能影响预后并对治疗至关重要。丧失 在抑制SHH信号传导（PTCH 1）的基因中观察到功能突变，在受体SMO（例如SmoM 2）中观察到激活突变，以及与TP 53缺失相关的效应基因GLI 2及其靶标的扩增。目前的HH抑制剂仅对一小部分MB有效，所有患者都会产生耐药性。我们推测SHH-MB内的一些肿瘤间异质性是由于它们来自不同的细胞谱系，在不同的时间，在CB的不同解剖区域。此外，细胞和转录 从不同来源细胞遗传的状态在成熟肿瘤中得以维持，并且可以代表治疗的靶点。因此，小鼠模型的基础研究方法是必要的，作为转化研究的基础。我们已经研究了SHH-GLI通路在哺乳动物发育中的20年，重点是CB。最近，我们开发了Ptch 1或Smo突变的散发性MB模型。值得注意的是，在每个模型中的肿瘤进展期间观察到可再现但不同的组织学。此外，在早期阶段观察到的大多数病变消退，并且与进展为MB的病变具有不同的细胞表型。我们建议：目标1。在2个发育阶段和谱系开始的Ptch 1和SmoM 2模型的标记物分析和纵向Mn增强MRI（Turnbull），并鉴定影响SHH-MB进展的候选内在基因（RNA-seq分析）。目标2.定义微环境并测试肿瘤相关的小胶质细胞和巨噬细胞如何影响SHH-MB进展。目标3。确定在目标1/2、mTOR信号传导或NR 2F 2中鉴定的选择候选基因是否改变SHH-MB进展，并将结果与人SHH-MB数据集（Taylor）和肿瘤样品进行比较。我们在小鼠模型中对MB进展的实验研究将与人类MB研究协同作用，并应有助于SHH亚组患者的分层，其中可以测试针对驱动MB进展的重要途径的新疗法，改善生存者的预后和生活质量。