THU556 Targeting Breast Cancer Stem Cells With Oncolytic Virus

Disclosure: N.I. Roman Ortiz: None. P. Danthi: None. J.H. Ostrander: None. Breast cancer is the second leading cause of cancer deaths among women in the United States. Estrogen receptor positive [ER+] breast cancer has a more favorable prognosis; however, patients can experience recurrence for many years after initial diagnosis. Breast cancer stem cells (BCSC), which are dormant and exist as a minority sub-population (0-5%), drive recurrence, metastasis and resistance to therapies that primarily target rapidly proliferating tumor cells. Current treatments are insufficient to cure metastatic ER+ breast cancer and there are no FDA approved therapeutics that target BCSC. Mammalian orthoreovirus (MRV) is an oncolytic virotherapy tested in clinical trials for many cancer types including metastatic breast cancer. MRV was found to be safe, but efficacy limited as a monotherapy. In our studies we compared several laboratory MRV strains (T1L, R2) to the strain most similar to Reolysin, which is being tested in clinical trials (i.e. T3D). Our studies suggest that T3D is less effective in killing ER+ breast cancer cells and BCSCs. We propose to generate a novel MRV strain with enhanced BCSC-targeting capacity using forward genetic approaches by serially passaging MRV strains in BCSC enriched 3D tumorsphere cultures of MCF-7 Paclitaxel resistant (TaxR) cells to generate a selective oncolytic virus. Preliminary data has shown that serially passaged (SP) MRV strains (T1L SP, R2 SP) are more effective in decreasing cell viability and inhibiting tumorsphere formation compared to the parental (P) strains (T1L P, R2 P). We anticipate these studies will lead to an improved MRV oncolytic virotherapy that will be combined with clinically relevant inhibitors, such as CDK4/6 inhibitors and anti-estrogens, to prevent and treat therapy-resistant ER+ breast cancer. Presentation: Thursday, June 15, 2023