# Production and progression of premalignant retinoblastoma lesions.

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2024 · $560,196

## Abstract

Project Summary
Most cancers develop from premalignant lesions that progress to malignancy in response to further mutations
or epigenetic changes. A better understanding of malignant progression may enable approaches to suppress
tumorigenesis, especially in individuals with specific cancer predispositions. This project aims to define
mechanisms through which premalignant lesions form and progress to malignancy in the childhood retinal
cancer, retinoblastoma. In this cancer, biallelic loss of RB1 is thought to enable the aberrant proliferation of early
maturing cone precursors (emCPs), which then form largely quiescent premalignant lesions in utero, followed
by emergence of retinoblastoma foci in the perinatal and postnatal periods. The earliest retinoblastomas appear
to lack clonal mutations beyond RB1, implying that entrance into and escape from premalignancy is enabled by
epigenetic changes. In preliminary studies, we developed stem cell-derived retinal organoid models that display
initial emCP proliferation, a largely quiescent premalignant stage, and emergence of retinoblastoma-like foci at
tissue ages similar to those of retinoblastomas in patients. Accordingly, the models provide an opportunity to
define mechanisms underlying the production and progression of premalignant retinoblastoma in an
experimentally tractable setting. Although numerous aspects may be considered, the project focuses on: a) the
emCPs’ proliferation dynamics and mitotic behavior at each tumorigenesis stage, along with gene expression
changes that overcome initially highly impaired mitoses to enable production of premalignant lesions; b) gene
expression changes that mediate exit from the cell cycle into a series of premalignant cell states; c) gene
expression and underlying epigenetic changes that mediate transitions between premalignant states and the
emergence of retinoblastoma-like foci, and finally d) characterization of the retinal organoid-derived
retinoblastoma-like foci, including definitive tests of their emCP origin, their malignant potential, and their
similarity to retinoblastomas in patients. Together, the studies aim to provide sufficient knowledge of malignant
progression to enable approaches to prevent this process in children with highly penetrant retinoblastoma
predisposition.

## Key facts

- **NIH application ID:** 10981387
- **Project number:** 2R01CA137124-12A1
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** David Cobrinik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $560,196
- **Award type:** 2
- **Project period:** 2011-03-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981387

## Citation

> US National Institutes of Health, RePORTER application 10981387, Production and progression of premalignant retinoblastoma lesions. (2R01CA137124-12A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10981387. Licensed CC0.

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