# Developmental transcription factors in Drosha-driven cancer

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $447,405

## Abstract

PROJECT SUMMARY/ABSTRACT
Pineoblastoma is one of a family of childhood cancers that can arise through mutations in
microRNA processing genes DROSHA and DICER1. It is unknown whether these tumors
develop through shared or distinct oncogenic pathways, and there are no ways to
therapeutically target such mutations. To understand how these mutations cause cancer, we
developed a mouse model of pineoblastoma by ablating Drosha or Dicer1 in the developing
pineal gland. These mice develop tumors that resemble human pineoblastoma. They are highly
proliferative; they exhibit an expression signature of the embryonic pineal gland; and they
overexpress microRNA target genes. Among the microRNA target genes overexpressed in
these tumors is a set of developmental transcription factors, including Onecut2. Furthermore,
the binding sequences recognized by these transcription factors is enriched in regions of open
chromatin in these pineal tumors. In this project, we will investigate the role of Onecut2 in the
developing pineal gland and in pineal tumor development. In Aim 1, we test whether Onecut2 is
necessary for tumor development. In Aim 2, we investigate how Onecut2 interacts with other
neurodevelopmental transcription factors. In Aim 3, we explore whether ONECUT2 is required
in patient-derived models of pineoblastoma. If successful, this project would demonstrate that
mutations in DROSHA or DICER1 can arrest differentiation through developmental transcription
factors and that impairing the activity of these transcription factors could be a future therapeutic
strategy.

## Key facts

- **NIH application ID:** 10856957
- **Project number:** 1R01CA289259-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Kenneth Sung-Man Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $447,405
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10856957

## Citation

> US National Institutes of Health, RePORTER application 10856957, Developmental transcription factors in Drosha-driven cancer (1R01CA289259-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10856957. Licensed CC0.

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