# Inhibition of Radiation-Induced Salivary Gland Fibrosis by Targeting Copper Metabolism

> **NIH DE R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2026 · $597,722

## Abstract

ABSTRACT
A first-line treatment for head and neck cancer is radiation therapy, but ionizing radiation can lead to chronic oral
complications such as fibrosis of the salivary glands (SG) and xerostomia. Therapeutic strategies to restore SG
function include gene therapy, stem cell transplantation and various bioengineering approaches; however, they
are dependent on the presence of residual functional SG tissue, a condition not met with full radiation treatment
due to extensive fibrotic coverage of the SG. Although a role for Lysyl Oxidase (LOX) in radiation-induced fibrosis
has not been investigated in SG, it is notable that each LOX family member has been implicated in various
fibrotic disorders affecting a wide range of organs. This has prompted efforts to develop monoclonal antibodies
targeting specific LOX enzymes; however, recent Phase II clinical trials of a monoclonal antibody against Lysyl
Oxidase-Like (LOXL2) failed to show efficacy against primary sclerosing cholangitis. These findings underscore
the importance of considering functional redundancy when targeting individual LOX and since the catalytic site
of all LOX family members possesses a conserved binding site for copper (Cu), focusing on inhibition of Cu
delivery to these enzymes is a novel antifibrotic strategy. Preliminary studies have identified a novel compound,
MKV3, as a potent inhibitor of the ATP7A copper transporter. Furthermore, ATP7A trafficking to the plasma
membrane enhances LOX activity in cancer cells which is blocked by MKV3. Ionizing radiation was found to
stimulate Cu-dependent ATP7A trafficking in rat parotid Par-C10 cells and that copper modulators, such as
tetrathiomolybdate (TTM) and MKV3, block this process. To extend these findings to in vivo studies, preliminary
results indicate that radiation treatment not only triggers Cu-dependent ATP7A trafficking in mouse
submandibular glands (SMG) from the perinuclear region to the plasma membrane but also causes collagen
deposition of ex

## Key facts

- **NIH application ID:** 11310016
- **Project number:** 5R01DE034293-03
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Olga Juliana Baker; MICHAEL J. PETRIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** DE
- **Fiscal year:** 2026
- **Award amount:** $597,722
- **Award type:** 5
- **Project period:** 2024-08-01T00:00:00 → 2029-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11310016

## Citation

> US National Institutes of Health, RePORTER application 11310016, Inhibition of Radiation-Induced Salivary Gland Fibrosis by Targeting Copper Metabolism (5R01DE034293-03). Retrieved via AI Analytics 2026-07-09 from https://api.ai-analytics.org/grant/nih/11310016. Licensed CC0.

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