201. The Engineered Drug 3′UTRMYC1-18 Degrades the c-MYC-STAT5A/B-PD-L1 Complex In Vivo to Inhibit Metastatic Triple-Negative Breast Cancer.
- Author
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Awah, Chidiebere U., Mun, Joo Sun, Paragodaarachchi, Aloka, Boylu, Baris, Ochu, Chika, Matsui, Hiroshi, and Ogunwobi, Olorunseun O.
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BREAST cancer prognosis , *THERAPEUTIC use of antineoplastic agents , *RESEARCH funding , *CANCER invasiveness , *BREAST tumors , *TRANSCRIPTION factors , *TREATMENT effectiveness , *IN vivo studies , *METASTASIS , *MESSENGER RNA , *NUCLEOTIDES , *MICE , *ANIMAL experimentation , *DRUG development , *SURVIVAL analysis (Biometry) , *DRUG tolerance , *SEQUENCE analysis , *DISEASE progression - Abstract
Simple Summary: The overexpression of c-MYC is implicated in many cancers, and it drives the tumors' aggressiveness and metastatic progression, but there is no clinically approved drug that targets MYC. We discovered that the MYC mRNA is stabilized by the poly U sequences on its 3′UTR. We engineered these stable elements into unstable forms in a way such that they degraded the target MYC mRNA through a process called nonsense-mediated decay. We developed the drug 3′UTRMYC1-18 and evaluated its therapeutic efficacy in a metastatic model of c-MYC-driven TNBC in vivo by delivering it with iron oxide nanocages. The constructs inhibited primary and metastatic lung and liver cancers by degrading the c-MYC-STAT5A/5B-PD-L1 complex and achieved significant survival outcomes. The in vivo data strongly suggests that this new drug is therapeutically effective in inhibiting c-MYC-driven triple-negative breast cancer and metastatic tumors. The drug was well tolerated and represents a new arsenal to target the deadly TNBC and will offer hope to patients who need it. c-MYC is overexpressed in 70% of human cancers, including triple-negative breast cancer (TNBC), yet there is no clinically approved drug that directly targets it. Here, we engineered the mRNA-stabilizing poly U sequences within the 3′UTR of c-MYC to specifically destabilize and promote the degradation of c-MYC transcripts. Interestingly, the engineered derivative outcompetes the endogenous overexpressed c-MYC mRNA, leading to reduced c-MYC mRNA and protein levels. The iron oxide nanocages (IO-nanocages) complexed with MYC-destabilizing constructs inhibited primary and metastatic tumors in mice bearing TNBC and significantly prolonged survival by degrading the c-MYC-STAT5A/B-PD-L1 complexes that drive c-MYC-positive TNBC. Taken together, we have described a novel therapy for c-MYC-driven TNBC and uncovered c-MYC-STAT5A/B-PD-L1 interaction as the target. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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