# Development of a RUVBL1/2 Inhibitor as a Radiosensitizer and Immune Stimulator for NSCLC

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $523,830

## Abstract

Lung cancer is the second most common malignancy and the leading cause of cancer-related death in both men
and women in the United States, and non-small cell lung cancer (NSCLC) accounts for ~85% of all cases.
Localized and regional NSCLC are frequently treated with external beam radiation therapy alone or in
combination with surgery and chemotherapy using platinum-based drugs and taxanes. Metastatic NSCLC is
typically treated with systemic therapies such as chemotherapy, targeted molecular therapies, immune
checkpoint inhibitors alone or in combination. Chemotherapy and targeted molecular therapies do not offer
durable complete responses for metastatic disease, which can be achieved only in the minority of patients with
immune checkpoint inhibitors. Also, recurrence is common for localized and regional NSCLC treated with
radiation therapy (RT). RT has cytotoxic activity by causing DNA damage in NSCLC cells but is limited by intrinsic
cellular mechanisms that repair DNA damage and confer resistance to RT. Thus, there is a need for novel agents
to overcome DNA repair mechanisms and enhance the therapeutic efficacy of RT in NSCLC and increase the
response rates for immune checkpoint inhibitors. We propose that the inhibition of the ATPases RUVBL1 and
RUVBL2 with an orally available inhibitor is an effective and cancer-selective strategy for radiosensitization that
efficiently blocks DNA repair pathways by reducing protein levels of three key DNA damage repair factors, DNA-
PKcs and ATM/AR, in NSCLC cells but not in normal cells. Because of that unique activity, we expect that the
RUVBL1/2 inhibitor will be more effectively enhance the antitumor effects of IR than specific DNA-PKcs/ATM/AR
in vitro and in vivo and elicit less radiotoxicity. Also, we propose that the RUVBL1/2 inhibition elicits immune
stimulation, and therefore will therapeutically synergize with IR and immune checkpoint inhibitors. This project
will (1) determine the efficacy, specificity and determinants of radiosensitization by RUVBL1/2 inhibition, (2)
characterize immune stimulatory effects of RUVBL1/2 inhibition alone and in combination with radiation, and (3)
study the therapeutic potential of RUVBL1/2 inhibition in combination with IR and immune checkpoint inhibition.
If our project is successfully completed, it may provide the framework for a new therapeutic strategy for NSCLC
patients, which could improve clinical outcomes for this hard-to-treat disease.

## Key facts

- **NIH application ID:** 10844619
- **Project number:** 5R01CA276058-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Esra Akbay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $523,830
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844619

## Citation

> US National Institutes of Health, RePORTER application 10844619, Development of a RUVBL1/2 Inhibitor as a Radiosensitizer and Immune Stimulator for NSCLC (5R01CA276058-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10844619. Licensed CC0.

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