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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

基本信息

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
项目类别：
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

项目摘要

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