Adenoid cystic carcinoma (ACC) is a type of cancer that originates in the glands of the body, but most commonly those of the head and neck responsible for saliva production. It is a rare tumor, but one that is highly lethal and very difficult to manage. One of the challenges in managing ACC tumors is that they are very slow growing, and new tumors often arise many years after the removal of the original tumor mass. This cancer has a high propensity to grow back and to spread silently throughout the body over many years. Thus, once a person has been diagnosed with ACC, surveillance for new tumors anywhere in the body is required on a routine basis for the remainder of the patients’ life. Despite these efforts, a high percentage of patients develop metastases and ultimately succumb to the disease. The prognosis for ACC patients is poor, with a 10-year overall survival rate of less than 40% and a 20-year overall survival rate of approximately 15%. Unfortunately, there is no effective treatment for ACC, and radical surgery to remove the tumor and surrounding tissues, followed by extensive radiation and chemotherapy has been the mainstay approach for many decades.

This proposal will evaluate a novel therapy in the form of cancer killing (oncolytic) viruses for the management of ACC tumors. Our laboratory has identified a feature that is unique to ACC tumors, which can be used to turn the tumor’s biology against itself and drive its own demise. ACC tumors arise because of aberrations at the chromosome level that result in the over-expression of a tumor-promoting gene called MYB. We used this chromosomal rearrangement to force tumor cells to express a gene that will cause cellular death (suicide gene), rather than promote tumor progression. We accomplish this by infecting tumor cells with the oncolytic viruses that can then introduce this suicide gene into the cells, under the control of the ACC tumor-specific chromosomal feature. To further enhance the potency of our therapeutic viruses we have designed and prototyped novel virus biology that increases the selectivity of the oncolytic viruses for epithelial cells, the cell type from which ACC tumors arise. Our laboratory has the laboratory models, as either ACC cell lines, gland tissue cultures, or animal models of ACC that can be used to refine the oncolytic virus technology proposed.

This project tests the hypothesis that the ACC tumor specific requirement for high MYB gene expression can be harnessed as a vulnerability to induce tumor cell death through an oncolytic virus approach. We have designed experiments to test this hypothesis in three specific aims. Aim 1 will evaluate our choice of suicide gene and test the specificity of the MYB chromosomal feature to kill ACC tumor cells in the laboratory. Aim 2 will test our modifications to the viral particles to assess their potency for ACC tumor infection in vivo. Finally, Aim 3 will test the oncolytic virus technology in ACC tumors in mice, evaluating the effect of this therapy on tumor and survival of the animals.