# Modeling Retinoblastoma Initiation Using 3D-Retinal Organoids

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $410,606

## Abstract

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.

## Key facts

- **NIH application ID:** 10165672
- **Project number:** 5R01CA245508-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Michael A Dyer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,606
- **Award type:** 5
- **Project period:** 2020-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165672

## Citation

> US National Institutes of Health, RePORTER application 10165672, Modeling Retinoblastoma Initiation Using 3D-Retinal Organoids (5R01CA245508-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10165672. Licensed CC0.

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