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.

项目概要 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 正在发育的视网膜称为视网膜母细胞瘤。与此同时，临床前测试和临床研究的进步带动了 改善患有这种毁灭性疾病的儿童的治疗结果。尽管取得了这些进步，但仍然存在 视网膜母细胞瘤领域的基本问题仍未得到解答。视网膜细胞是否已完全转化 一旦它们维持 RB1 基因的双等位基因失活或者视网膜母细胞瘤肿瘤发生是多阶段的 过程？为什么一些具有相同种系RB1突变的家庭成员会出现双侧多灶性病变 年轻时患有视网膜母细胞瘤，而其他人却没有疾病证据？治疗能否引发一个过程 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进行活检，仅进行摘除术 对于晚期眼睛。为了克服该领域的这一障碍，我们开发了第一个 使用从患有以下疾病的患者身上产生的 3D 视网膜类器官建立自发性人类视网膜母细胞瘤肿瘤模型 种系 RB1 突变。我组建了一支多学科团队，拥有计算和干方面的专业知识 细胞生物学、肿瘤学、病理学、流行病学和生物统计学使用这种创新的新模型 视网膜母细胞瘤回答 3 个具体目标的基本问题。我们将确定是否存在视网膜母细胞瘤 如果分子、细胞或遗传因素有助于 外显率和表达率的差异（目标 2）以及治疗是否存在克隆选择（目标 3）。我有 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有着良好的记录。这 该提案将通过新型维持疗法的临床前测试影响视网膜母细胞瘤患者 （目标 3）防止在完成手术后的最初几个月内周边视网膜形成新的肿瘤 化疗。它还可能有助于识别具有种系 RB1 突变的视网膜母细胞瘤幸存者的子集 患有第二种恶性肿瘤的风险极高，需要更广泛的癌症筛查（目标 2）。没有其他中心拥有可用于执行所提出的研究的团队、资源、专业知识或工具 在这里，有效地将最有希望的发现直接转移到临床试验中。