Abstract 2765: Combination ONC201 and radiation therapy in the treatment of breast cancer

Purpose: Metastatic breast cancer patients continue to have poor outcomes on current treatments, and thus, novel therapies in combination with standard treatments are needed. Towards this we studied the pre-clinical effects of combining ONC201, a first-in-class imipridone (which works via activation of ER stress, upregulation of TRAIL, and activation of death receptor 5 [DR5]) with radiation therapy (RT). Since the DR5 pathway is also required for RT-induced apoptosis, we hypothesized that addition of ONC201 could increase the effectiveness of RT. Pertinent Experimental Procedures: Human and mouse breast cancer cell lines were used to study in vitro cancer cell death (by AlamarBlue and clonogenic assays). Patient-derived breast cancer tissue and mouse cell lines were used to study in vivo tumor growth kinetics. Cell lines and mice were administered radiation (0-8 Gy) delivered via a Gammacell 40 exactor. ONC201 was given at does 0-10 µM. Mechanisms of tumor cell death were elucidated using western blots of cleaved PARP (cPARP) and caspase 3 (cC3). Immune response mechanisms were elucidated using in vivo cell-specific depletion. Summary of Data: Multiple breast cancer lines (MB231, MB468, and 4T1) exhibited decreased cell viability after combination therapy compared to either single therapy. In particular, ON201 (1 µM) followed by RT (8 Gy) resulted in a decreased MB468 breast cancer cell viability compared to no treatment (36.9%, P