# Successive responses to oncogenic aberrations in retinoblastoma genesis.

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2023 · $322,416

## Abstract

Project Summary
Understanding how a normal cell becomes a malignant cancer may provide new therapeutic and prevention
opportunities. However, although many genetic changes that promote cancer have been identified, and the
corresponding signaling pathways elucidated in model settings, the cellular responses that mediate oncogenic
transformation in an authentic human cancer cell-of-origin are largely unexplored. This study aims to define
cellular responses that mediate the development of a childhood eye cancer, retinoblastoma, which is well
suited to such analyses because the cell-of-origin (the maturing cone precursor), the major initiating mutation
(biallelic RB1 inactivation), and an indolent pre-malignant stage have been identified, and because the cell-of-
origin’s proliferative response to initiating oncogenic mutations, progression through a pre-malignant state, and
emergence as a retinoblastoma tumor can be observed and characterized in in vitro and in vivo assays. The
proposed studies will explore the successive gene expression and cell signaling changes that underlie the
cone precursors’ responses to RB1 loss, including changes that mediate cell cycle entry, proliferation, retreat
to an indolent pre-malignant state, and either deactivation to form a senescence-like retinoma or reactivation to
form a highly proliferating retinoblastoma mass. Aim 1 will define the transcriptomic changes that occur in
response to RB loss as the cone precursor cell of origin embarks on its malignant trajectory in the developing
retina. Aims 2 and 3 will focus on recently identified early gene expression responses and their importance for
cone precursor proliferation and traversal of the pre-malignant phase. Aim 2 centers on the up-regulation of an
oncogenic epigenetic regulator, which may enable reactivation of indolent, pre-malignant cone precursors and
emergence of retinoblastoma tumors. Aim 3 centers on the down-regulation of a negative regulator of PI3-
kinase signaling, which may enhance the RB-deficient cone precursor survival and transformation. Aim 4 will
focus on the RB structures, biochemical functions, and downstream mechanisms that are needed to suppress
cone precursor cell cycle entry and traversal of the pre-malignant phase. Particular attention will be paid to the
stages at which different RB functions contribute to suppress retinoblastoma and the gene expression and cell
signaling changes that mediate RB effects. Together, the proposed studies are expected to improve
understanding of the oncogenic responses of a human cancer cell-of-origin during its journey towards
malignancy. In turn, the improved understanding may reveal vulnerabilities that can be targeted in order to
prevent retinoblastoma in genetically predisposed children.

## Key facts

- **NIH application ID:** 10582627
- **Project number:** 5R01CA137124-11
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** David Cobrinik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $322,416
- **Award type:** 5
- **Project period:** 2011-03-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582627

## Citation

> US National Institutes of Health, RePORTER application 10582627, Successive responses to oncogenic aberrations in retinoblastoma genesis. (5R01CA137124-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10582627. Licensed CC0.

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