Development and characterization of metastatic Myb-NFIB fusion adenoid cystic carcinoma cell line models

Salivary gland adenoid cystic carcinoma (ACC) is a rare but deadly disease that is well controlled in the head and neck with surgery and radiation. However, in over 50% of patients, distant metastasis will develop, yet there are no approved chemotherapy or targeted agents suitable for treatment when this occurs. Up to 70% of ACCs have an alteration or gene fusion in the oncogene Myb, mostly combining with the transcription factor NFIB. This unique gene fusion event can have multiple different breakpoints, and therefore can produce several different protein products. Unfortunately, little is known about the oncogenic function of these gene fusions, and currently, there are no drugs targeting Myb or the fusion protein specifically. Broadly speaking, when these unusual fusion events occur in cancer, they often represent key molecular changes that are critical to the function of that cancer and can be exploited for drug targets. Few research models exist to help study this cancer and better understand why it is so aggressive. In order to advance the field and identify new drugs for treatment, it is imperative to analyze the function of these new fusion proteins. We have created cell line models with 5 different fusions and have discovered that we can inject these into the tail veins of mice to create lung metastases. Interestingly, in our early studies, the different fusions appear to have a range of aggressiveness. We would like to better characterize these different fusion types by also injecting these cells into mouse salivary glands to create situations where the cancer cells can behave more like they do in humans. We can then perform analyses on how these different fusions are behaving in these situations through RNA sequencing. This technique will provide deep insight into what pathways are changed and expose what vulnerabilities might exist within the cells with fusions. The main cause of mortality in ACC is distant metastasis, predominantly in the lung. Unfortunately, there are no proven drugs that help patients with ACC when this occurs. We have developed the first animal model for metastasis and intend to create a viable orthotopic PDX model. Additionally, little is known about the Myb-NFIB fusion proteins and how they contribute to carcinogenesis. Thus, this proposal seeks to combine our innovative animal models along with the Myb fusion to both provide model systems to understand the function of Myb- NFIB and create a platform for drug testing. These findings will greatly accelerate the rational identification of drug targets in ACC and help fast track them by testing in our model system. Rather than testing of borrowed drugs from other cancer models, we can focus our attention on ACC-specific compounds and help patients afflicted with this deadly cancer. Project Number: 1R21DE035273-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Patrick Ha | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $451,000 | Activity Code: R21 | Study Section: Tumor Evolution, Heterogeneity and Metastasis Study Section[TEHM] View on NIH RePORTER: https://reporter.nih.gov/project-details/11214279