Cancers of the head and neck represent a major cause of morbidity and mortality in our society. Salivary glands are organs that produce saliva such as parotids and submandibular glands. These glands can also develop into many type of cancers, one of which is acinic cell carcinoma (AcCC). AcCC is treated by surgical resection followed by radiation therapy if there are risk factors such as positive margins or lymph node spread. However, when AcCC becomes metastatic, there are no targeted or curative treatments available. In order to develop novel therapies against the AcCC, we set out to understand the biology and causes of how AcCC develops. We performed RNA-sequencing which allows us to profile the entire gene expression changes of the AcCC. Analysis of RNA-seq data also allows us to identify chromosomal translocations. Surprisingly, we detected recurrent, chromosomal translocations of a gene called NR4A3 or the related gene, NR4A2, which are nuclear receptor transcription factors. When the translocation occurs, the NR4A3 or NR4A2 gene becomes overexpressed because highly active enhancers relocate in close proximity to the NR4A3 or NR4A2 gene promoters, which instruct the gene to become active. Our results indicate that the majority, if not all, of AcCC tumors over-express either NR4A3 or NR4A2, suggesting that these nuclear receptors are the driver oncogenes for AcCC. Analysis of the RNA-seq data also identified subgroups within the cohort of AcCC samples, including a poor survival subgroup with a distinct gene expression profile and upregulation of both NR4A3 and c-Myb, another oncogenic transcription factor implicated in a variety of cancers including another type of salivary gland neoplasm, adenoid cystic carcinoma. These results led us to the hypothesis that the NR4A3 and NR4A2 genes are driver oncogenes for AcCC and represent novel therapeutic targets for the treatment of AcCC. In Specific Aim 1, we will determine how NR4A3 and c-Myb transcriptions factors interact to make AcCC more aggressive and prone to metastasis. In Specific Aim 2, we will develop AcCC tumor models to identify therapeutic targets for AcCC. Currently, there are no AcCC cell lines or animal models available. We will generate cell lines from mouse salivary glands that overexpress NR4A3 with or without c- Myb. The new cell lines will provide us with more relevant models to test novel therapeutic targets.

Currently, there are no curative treatments available in metastatic setting. Our research will help patients with recurrent or metastatic AcCC. Since NR4A3 is a nuclear receptor, it also holds the potential for development of small molecule inhibitors as novel treatments to improve the outcomes of AcCC patients. We project 3 years to complete the Specific Aims 1 and 2. If we can identify drugs already in clinical use that can be repurposed for the treatment of AcCC, then we envision more rapid clinical translation to help patients with AcCC. The results of our research will not only contribute to advancing our understanding of the biology and etiology of AcCC, but also provide more relevant AcCC cell lines to other researchers for their use. In addition, our results will be relevant to other rare cancers such as extraskeletal myxoid chondrosarcoma which NR4A3 plays an important role.