# Mechanisms of Adenoid Cystic Carcinoma Development and Tumor Maintenance

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $364,562

## Abstract

PROJECT SUMMARY
Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands. Over 60% of the
ACC patients succumb to the disease within 15 years from diagnosis. The lack of reliable experimental models
for ACC has limited our progress in understanding the biology of the disease and the proliferation of preclinical
studies to test new therapies. In this proposal we address this fundamental need by proposing the generation of
genetically engineered mouse models that develop autochthonous ACCs. These mice will help determine the role
of molecular alterations frequently found in human ACCs and will generate an in vivo platform for molecular
and preclinical studies that will help advance towards more effective therapies to treat ACC patients. MYB is by
far the most commonly altered gene in human ACCs, as over 70% of the tumors overexpress MYB-NFIB fusions
or the full-length MYB. Our preliminary studies show that MYB overexpression in transgenic mice induces ACCs
with long latency, indicating that MYB promotes ACC development, but also suggesting that additional
alterations are required for ACC development. Genetic alterations affecting MYB-unrelated genes are found at
lower frequencies in human ACCs. Notably, mutations in different genes that are predicted to result in activation
of NOTCH signaling, including activating mutations in NOTCH1, were found in 25%-35% of the human ACCs,
associated with poor prognosis. Of those, inactivating mutations in the SPEN gene were found in ~20% of the
ACCs. SPEN is a transcriptional repressor of NOTCH signaling and functions as a tumor suppressor through
NOTCH-dependent and NOTCH-independent mechanisms. Importantly, these mutations co-exist with MYB
alterations, but their contribution to ACC development is presently unknown. In this proposal we will analyze
the cooperation of MYB with NOTCH activation or SPEN inactivation during ACC development, in mouse models
that allow the activation of mutations in salivary glands. The inducible nature of the system used to activate these
alterations will allow us to determine whether they are required to maintain tumor growth and to identify
mechanisms involved in tumor regression. Analysis of the transcriptomes of the tumors that develop in these
mice will allow us to identify MYB-regulated genes and pathways that contribute to ACC development, some of
which may be required to maintain tumor growth, and thus could be excellent targets to explore new therapies
for ACC.

## Key facts

- **NIH application ID:** 10071080
- **Project number:** 5R01DE026735-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** CARLOS CAULIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $364,562
- **Award type:** 5
- **Project period:** 2018-06-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071080

## Citation

> US National Institutes of Health, RePORTER application 10071080, Mechanisms of Adenoid Cystic Carcinoma Development and Tumor Maintenance (5R01DE026735-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071080. Licensed CC0.

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