# Advancing Cancer Therapy through Groundbreaking Research in Radiation Biology

> **NIH NIH R35** · DUKE UNIVERSITY · 2022 · $950,637

## Abstract

PROJECT SUMMARY/ABSTRACT
Radiation therapy is utilized to treat approximately half of all cancer patients. For some patients,
radiation therapy can achieve local tumor control and cure. For other patients, radiation therapy
palliates symptoms and alleviates suffering. However, radiation therapy can also cause acute toxicity
and late effects that diminish quality of life. The goal of our research program is to widen the
therapeutic window of radiation therapy by dissecting mechanisms of normal tissue radiation injury and
tumor response to radiotherapy. As I am a sarcoma radiation oncologist, my research group not only
studies sarcoma response to radiation therapy, but also sarcoma development and metastasis. During
the prior funding period, we adapted CRISPR/Cas9 technology to develop novel genetically engineered
mouse models of sarcoma that facilitated lineage tracing of sarcoma clones during tumor progression.
This approach identified novel regulators of metastasis, which are potential targets for new cancer
therapies. We also used new mouse and in vitro models to discover a novel mechanism for the
exquisite radiosensitivity of myxoid liposarcoma: DNA-damage induced phosphorylation of a prion-like
domain in the FUS-CHOP fusion protein disrupts interactions with chromatin remodeling complexes
that are required for tumor maintenance. We initiated new projects with a novel sarcoma model with
high tumor mutation burden that revealed tumor-intrinsic and immune-mediated mechanisms of
response and resistance to radiotherapy and immunotherapy. Our findings provided the rationale for a
randomized clinical trial in sarcoma patients testing radiation therapy with immune checkpoint inhibition.
We also used our genetically engineered mice to uncover mechanisms regulating acute toxicity and
late effects of radiation, such as radiation carcinogenesis. Our proposed research will build on the
success of our recent work. We will use innovative model systems and sophisticated approaches to
make discoveries in three broad areas:
1. Response of sarcomas to radiotherapy
2. Response and resistance of sarcomas to radiation and immunotherapy
3. Normal tissue injury from radiation
The knowledge gained from the proposed studies will not only deepen our understanding of radiation
and sarcoma biology, but will also inform the design of future clinical trials that aim to widen the
therapeutic ratio of radiation therapy to improve the outcome for patients with sarcomas and other
cancers.

## Key facts

- **NIH application ID:** 10517545
- **Project number:** 2R35CA197616-08
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** David Guy Kirsch
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $950,637
- **Award type:** 2
- **Project period:** 2016-01-04 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10517545

## Citation

> US National Institutes of Health, RePORTER application 10517545, Advancing Cancer Therapy through Groundbreaking Research in Radiation Biology (2R35CA197616-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10517545. Licensed CC0.

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