# Dissecting the role of ATRX in soft tissue sarcoma development and radiation response

> **NIH NIH F30** · DUKE UNIVERSITY · 2020 · $37,649

## Abstract

ABSTRACT:
Soft tissue sarcomas are tumors of the connective tissue that account for an estimated 12,000 new
cancer cases annually and carry a poor prognosis with a five year survival rate of 50% despite treatment.
An important research objective in improving therapy for soft tissue sarcoma patients is to understand
how genetic mutations affect soft tissue sarcoma development and radiation response. Intriguingly, next-
generation sequencing data from The Cancer Genome Atlas and other massive cancer sequencing
efforts have identified Alpha Thalassemia and Mental Retardation X-linked, or ATRX, as the second most
frequently mutated gene in soft tissue sarcoma. ATRX is perhaps best known for its role as regulator of
alternative lengthening of telomeres (ALT), a telomerase independent tumor maintenance mechanisms
found in 15% of all human cancers. Interestingly, ATRX is predictive for overall survival in multiple
human cancers and researchers recently demonstrated that ATRX knockdown leads to radiosensitization
in glioma cell lines. Despite the clear importance of this gene in multiple human cancers and its frequent
alteration in soft tissue sarcoma, the role of ATRX in soft tissue sarcoma remains relatively unstudied.
The long term goal of this project is to improve the efficacy of current therapies for soft tissue sarcoma
patients and enable the development of novel therapeutics for the treatment of human cancers. The overall
goal of this proposal is to determine the effect of Atrx deletion on the radiosensitivity and innate immune
response of soft tissue sarcoma. To achieve this, the Cre-LoxP recombinase system has been used in
genetically engineered mouse models to generate the first primary mouse model of soft tissue sarcoma with
ATRX deletion. The central hypothesis is that loss of ATRX impairs DNA damage repair, delays tumor
development and increases radiosensitivity in soft tissue sarcoma. To test this hypothesis, primary soft
tissue sarcomas with ATRX deletion will be compared to primary soft tissue sarcomas that retain Atrx.
Using in vitro and in vivo model systems generated using Cre-LoxP and dual recombinase technologies, I
will test this hypothesis in three specific aims:
 Aim 1: Investigate the effect of Atrx deletion on tumor growth and repetitive element associated
 mitotic dysfunction in a primary mouse model of soft tissue sarcoma
Aim 2: Determine the role of ATRX in DNA damage repair and sarcoma response to ionizing radiation
Aim 3: Determine the effect of Atrx deletion on radiation induced mitotic dysfunction and cGAS-STING
innate immune signaling in sarcoma

## Key facts

- **NIH application ID:** 9905023
- **Project number:** 1F30CA232652-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Robert Warren Floyd
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,649
- **Award type:** 1
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905023

## Citation

> US National Institutes of Health, RePORTER application 9905023, Dissecting the role of ATRX in soft tissue sarcoma development and radiation response (1F30CA232652-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9905023. Licensed CC0.

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