# Impact of Host NF-kB Signaling in Radiation Therapy

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $357,634

## Abstract

PROJECT SUMMARY / ABSTRACT
Investigation of cytoplasmic-to-nuclear (C→N) NF-κB signaling pathways induced by various cell surface
receptors has significantly expanded the knowledge regarding the role of this transcription factor family in
regulating immune/inflammatory responses and tumorigenesis. By contrast, the physiological role of DNA
damage-induced nuclear-to-cytoplasmic (N→C) NF-κB signaling remains poorly understood. The proposed
study will fill this knowledge gap by elucidating a surprising and crucial role of N→C NF-κB signaling in sustaining
anti-tumor CD8 T cell responses during radiotherapy (RT) in vivo. The current proposal utilizes a genetically
modified mouse model that selectively disables N→C NF-κB signaling in vivo. Our preliminary data show that
radiation therapy can induce sustained regression of syngeneic tumors in a manner dependent on CD8 T cells.
We also found that a special type of memory CD8 T cells implicated in tumor control is expanded in this mouse
model. Finally, we have generated an encouraging data with an NF-kB DNA binding inhibitor to induce sustained
tumor regression following radiation therapy. Based on these observations, we hypothesize that inhibition of
N→C NF-κB signaling in the host improve radiation therapy via generation of tumor antigen-specific memory
CD8 T cells. We will test this hypothesis by define the cellular mechanism of sustained tumor control mediated
by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 1), elucidate the molecular mechanism of
sustained tumor control mediated by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 2) and target
host N→C NF-κB signaling with a chemical inhibitor to improve radiation therapy (Aim 3). The proposed study is
significant because the physiological role of N→C NF-κB signaling in modulating host tumor response is
completely undefined and this study will fill this knowledge gap. It is innovative because a new mouse model and
a novel chemical inhibitor currently undergoing Phase 2 clinical trials will be employed. Finally, a high impact is
expected because chemical targeting of N→C NF-κB signaling by the above inhibitor may expedite timely
translation to clinical trials.

## Key facts

- **NIH application ID:** 10872255
- **Project number:** 5R01CA246321-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SHIGEKI MIYAMOTO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $357,634
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872255

## Citation

> US National Institutes of Health, RePORTER application 10872255, Impact of Host NF-kB Signaling in Radiation Therapy (5R01CA246321-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10872255. Licensed CC0.

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