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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 Citation Format: Sachin R. Jhawar, Devora Schiff, Hao Wu, Aditya Thandoni, Suemair Hassan, Joshua Allen, Martin Stogniew, Rohinton Tarapore, Wolfgang Oster, Mark Stein, Ann W. Silk, Sharad Goyal, Bruce G. Haffty, Andrew Zloza. Combination ONC201 and radiation therapy in the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2765.

Talimogene laherparepvec (TVEC), an oncolytic virus, is an FDA-approved therapy that increases the overall survival of locally advanced and metastatic melanoma patients. Radiation therapy (RT) in combination with immunotherapies improves response rates (compared to either modality alone). Therefore, we hypothesized that combination RT and TVEC results in a synergistic therapeutic effect on melanoma. We treated 8 human melanoma cell lines with radiation (0, 4, or 8 Gy) and/or T-VEC (0, 0.01, 0.1, or 1 MOI) and determined its therapeutic effects using the AlamarBlue cell viability assay. Treatment of UACC257 melanoma cells with combination RT (8 Gy) and TVEC (1 MOI) resulted in a significant decrease in tumor cell viability (a decrease of 44.9%) compared to no treatment, RT alone (33.2%, P=0.0004), or T-VEC alone (24.2%, P=0.0088), with similar findings in other cell lines. We then injected a B16 mouse melanoma cell line, permissive to T-VEC infection, into B6 mice to assess in vivo synergy. Mice were treated when tumors were ~7mm × 7mm. RT resulted in an early 20% decrease in tumor size within 4 days, followed by an increase thereafter. Intra-tumoral TVEC resulted in no clear benefit until 9 days post-treatment, when it showed a slight decrease in size sustained for ~10 days. Combination treatment, however, led to an early response that was sustained until 18 days after the initial treatment. When tumors were assessed 18 days after initial treatment, a 3-fold or more increase in tumor size was lowest in the combination T-VEC + RT group (17%) compared to the control (100%), RT (60%), or TVEC (50%) groups. These data propose that combination T-VEC + RT may be beneficial for cancer patients, and studies establishing the mechanism of synergy are ongoing.