Modeling Retinoblastoma Initiation Using 3D-Retinal Organoids

使用 3D 视网膜类器官模拟视网膜母细胞瘤的发生

• 批准号: 10165672
• 负责人: Michael A Dyer
• 金额: $ 41.06万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10165672
• 关键词: 3-Dimensional; Address; Affect; Age; Basic Science; Benign; Bilateral; Biology; Biometry; Cancer Model; Cells; Child; Chromatin; Clinic; Clinical Research; Clinical Trials; Clonal Evolution; Clone Cells; Collection; DNA Methylation; Data; Disease; Epidemiology; Evaluation; Eye; Family; Family member; Frequencies; Future; Gene Expression; Genetic; Genetic Heterogeneity; Genetic study; Goals; Government; Head; Human; Individual; Knowledge; Laboratories; Lead; Lesion; Link; Loss of Heterozygosity; MYCN gene; Maintenance Therapy; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Medicine; Modeling; Molecular; Monitor; Mutation; No Evidence of Disease; Nucleotides; Oncogene Activation; Oncogenes; Oncology; Organoids; Outcome; Pathology; Patients; Penetrance; Peripheral; Persons; Preclinical Testing; Process; RB1 Gene Inactivation; RB1 gene; Reagent; Research; Research Proposals; Resolution; Resources; Retina; Retinoblastoma; SYK gene; Screening for cancer; Survivors; Testing; Treatment Failure; Treatment Protocols; Tumor-Associated Process; Vision; cancer genetics; chemotherapy; experimental study; high risk; in vivo; induced pluripotent stem cell; innovation; insight; mathematical model; multidisciplinary; neoplastic cell; novel; patient derived xenograft model; preservation; prevent; response; stem cell biology; tool; tumor; tumor progression; tumor xenograft; tumorigenesis

PROJECT SUMMARY Several landmark discoveries in cancer genetics have come from studies on a rare childhood cancer of the developing retina called retinoblastoma. In parallel, advances in preclinical testing and clinical research has led to improvements in outcome for children with this devastating disease. Despite these advances, there are still fundamental questions in the retinoblastoma field that remain unanswered. Are retinal cells fully transformed once they sustain biallelic inactivation of the RB1 gene or is retinoblastoma tumorigenesis a multistage process? Why do some family members with the same germline RB1 mutation have bilateral multifocal retinoblastoma at a young age while others have no evidence of disease? Can treatment induce a process of tumor cell clonal evolution and selection that leads to tumor progression and enucleation? These questions have been impossible to answer because retinoblastomas are not biopsied and enucleation is only performed for advanced stage eyes. In order to overcome this barrier in the field, we have developed the first spontaneous human retinoblastoma tumor model using 3D retinal organoids produced from patients with germline RB1 mutations. I have assembled a multidisciplinary team with expertise in computational and stem cell biology, oncology, pathology, epidemiology and biostatistics to use this innovative new model of retinoblastoma to answer fundamental questions in 3 specific aims. We will determine if retinoblastoma progresses through a multistep process (Aim 1), if molecular, cellular or genetic factors contributes to differences in penetrance and expressivity (Aim 2) and if there is clonal selection with treatment (Aim 3). I have a proven record in retinoblastoma genetics and of moving basic science discoveries into clinical trials. This proposal will impact patients with retinoblastoma through preclinical testing of a novel maintenance therapy (Aim 3) to prevent new tumors from forming in the peripheral retina in the first few months after completion of chemotherapy. It may also help to identify a subset of retinoblastoma survivors with germline RB1 mutations that have an ultra-high risk of developing a 2nd malignancy and require more extensive cancer screening (Aim 2). No other center has the team, resources, expertise, or tools available to perform the studies presented here and efficiently move the most promising findings directly into a clinical trial.

项目总结 癌症遗传学方面的几项里程碑式的发现来自对一种罕见的儿童癌症的研究 发展中的视网膜称为视网膜母细胞瘤。与此同时，临床前试验和临床研究的进步导致了 对患有这种毁灭性疾病的儿童预后的改善。尽管取得了这些进展，但仍有 视网膜母细胞瘤领域中尚未得到解答的基本问题。视网膜细胞是否完全转化 一旦他们维持了RB1基因的双等位基因失活，或者视网膜母细胞瘤的肿瘤形成是一个多阶段的 流程呢？为什么具有相同胚系RB1突变的一些家庭成员具有双侧多灶性 视网膜母细胞瘤在年轻的时候，而其他人没有疾病的证据？治疗会不会导致一种 导致肿瘤进展和去核的肿瘤细胞克隆进化和选择？这些问题 无法回答，因为视网膜母细胞瘤不做活组织检查，只做眼球摘除术 适合晚期眼睛。为了克服这一领域的障碍，我们开发了第一款 自发性人视网膜母细胞瘤模型的研究 胚系RB1突变。我已经组建了一个在计算和STEM方面具有专业知识的多学科团队 细胞生物学、肿瘤学、病理学、流行病学和生物统计学使用这一创新的新模式 视网膜母细胞瘤以3个具体目标回答基本问题。我们将确定视网膜母细胞瘤是否 通过多步骤过程(目标1)进行进展，如果分子、细胞或遗传因素有助于 外显率和表现力的差异(目标2)以及是否存在克隆选择和治疗(目标3)。我有过 在视网膜母细胞瘤遗传学和将基础科学发现转化为临床试验方面的公认记录。这 一项提案将通过一种新的维持疗法的临床前测试来影响视网膜母细胞瘤患者 (目标3)在完成手术后的头几个月内，防止在外围视网膜形成新的肿瘤 化疗。这也可能有助于确定视网膜母细胞瘤幸存者中具有胚系RB1突变的子集 具有发展为第二种恶性肿瘤的超高风险，需要更广泛的癌症筛查(AIM 2)。没有其他中心拥有团队、资源、专业知识或工具来执行所展示的研究 在这里，高效地将最有希望的发现直接转化为临床试验。