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

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2024 · $615,328

## 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 extracellular matrix, with these events being reduced by TTM. Finally, ATP7A localization was
found to be altered in the fibrotic SMG of irradiated patients, thus indicating a likelihood for clinical applications
of these findings. Based on the above, it is hypothesized that ionizing radiation triggers Cu-stimulated ATP7A
trafficking in SG, which facilitates the metalation of LOX enzymes leading to increasing collagen crosslinking and
fibrosis. Therefore, the following Aims are proposed: Aim 1 will elucidate the molecular mechanisms of altered
Cu homeostasis in irradiated SG. Aim 2 will evaluate the therapeutic potential of SMG-specific Atp7a gene
silencing on radiation-induced fibrosis and saliva secretion. Aim 3 will evaluate the therapeutic effects of
pharmacological targeting of copper transport on radiation-induced SMG fibrosis. Together, these studies will
demonstrate that targeting of Cu metabolism can be used as a novel treatment for radiation-induced SG fibrosis.

## Key facts

- **NIH application ID:** 10997711
- **Project number:** 1R01DE034293-01
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Olga Juliana Baker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $615,328
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997711

## Citation

> US National Institutes of Health, RePORTER application 10997711, Inhibition of Radiation-Induced Salivary Gland Fibrosis by Targeting Copper Metabolism (1R01DE034293-01). Retrieved via AI Analytics 2026-09-07 from https://api.ai-analytics.org/grant/nih/10997711. Licensed CC0.

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