# Determining the developmental origins of retinoblastoma

> **NIH NIH F32** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $67,446

## Abstract

Project Summary/Abstract
Retinoblastoma is the most common pediatric eye cancer and is caused by the biallelic inactivation of the
tumor suppressor gene RB1. There are between 200 and 300 new patients with retinoblastoma in the U.S.
each year, most diagnosed before two years of age. When caught early, and with proper care, survival from
retinoblastoma is relatively high. However, treatments, including enucleations, or removal of the eye, have
lasting effects on the lives of the children. Furthermore, retinoblastomas with extraocular involvement have a
much poorer prognosis. While animal models of retinoblastoma have been useful for preclinical and clinical
testing of retinoblastoma treatment, mice with loss of RB1 never develop retinoblastoma and therefore cannot
accurately recapitulate human retinoblastoma formation. This has led to gaps in our understanding of the
tumor initiation, development, and cellular specificity of human retinoblastoma.
The goal of this study is to use our new model of spontaneous human retinoblastoma using patient derived
iPSCs to study the developmental origin(s) of retinoblastoma and characterize the mechanisms of the second
hit mutation. We have generated 15 induced pluripotent stem cell (iPSC) lines derived from patients with
germline mutations in RB1. Using an optimized retinal differentiation culture, we have differentiated the patient
lines into retina, dissociated the organoids, injected the cells into mice to screen for tumor formation. The
resulting tumors have expression patterns similar to retinoblastoma patient derived xenografts. I now have a
model system to study retinoblastoma tumor formation during retinal differentiation. I will use our new
retinoblastoma reporter line in H9 hESCs, SYK-GFP, and a combination of immunostaining, single cell
sequencing and electron microscopy to determine cell of origin or retinoblastoma. Additionally, I will analyze
the tumors over multiple rounds of differentiation to determine the mechanism of the second hit and if there is
any genetic predisposition to the loss of heterozygosity that occurs in patients with germline RB1 mutations.
This study will allow us, for the first time, to answer question about retinoblastoma initiation and progression.
Defining the cell of origin or retinoblastoma and the mechanism of the second hit of RB1 will not only increase
our depth of understanding of retinoblastoma development but can be more generally applied to the
fundamental understanding of cancer initiation. Furthermore, the data provided by this study will hopefully
provide insight to create more targeted therapies for children with retinoblastoma.

## Key facts

- **NIH application ID:** 9891844
- **Project number:** 5F32CA225442-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Jacqueline Norrie
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891844

## Citation

> US National Institutes of Health, RePORTER application 9891844, Determining the developmental origins of retinoblastoma (5F32CA225442-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891844. Licensed CC0.

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