LAUSR

c-MYC is a master transcription factor overexpressed in more than 70% of human cancers including breast cancers (TNBC), lung cancers, brain tumors, prostate cancers, lymphomas, pediatrics cancers, pancreatic cancers, colorectal cancers, and ovarian cancers. Yet there is no clinically approved drug that directly targets it. The lack of direct clinically approved inhibitors of c-MYC is a significant biological and clinical question that needs urgent attention, especially in the context of aggressive cancers such as MYC driven triple negative breast cancer. In the USA, TNBC accounts for 10.34% of breast cancers, in China the rate is at 14%, and in African Americans the rate is 40%. We engineered the stable polyU sequences on the 3’UTR of c-MYC into unstable forms and specifically destabilized and degraded c-MYC transcript and protein and controlled primary tumor and metastasis in vivo. We developed three c-MYC destabilizing constructs that were effective in TNBC. They specifically destabilized c-MYC transcript, degraded c-MYC protein and the transcription factors STAT5A/B with increased expression of active caspase 3/7 leading to cancer cell death. In vivo, we delivered nanocage complexed with the MYC destabilizing constructs into TNBC mice bearing tumor and achieved reduction of primary tumor volume by 60-80%, 80% reduction in secondary tumor metastasis and very significant survival outcome (p<0.0001). Mechanistically, the destabilization of c-MYC degraded c-MYC and its super enhancer interacting partner, STAT5A/B, in primary tumors and metastatic tumors. Taken together, we have developed a novel therapy for TNBC and uncovered c-MYC super enhancer STAT5A/B interaction as the target Citation Format: Chidiebere U. Awah, Joo Sun Mun, Baris Boylu, Alooka Paragodaarachchi, Chika Ochu, Junfei Zhang, Hiroshi Mastui, Olorunseun Ogunwobi. Nanocage delivered engineered destabilized 3UTR ARE of cMYC inhibits triple negative breast cancer growth and metastasis in vivo by targeting cMYC and downregulating STAT5A5B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1459.