Dorji Jigme P, Chen Queenie, Perera Sandali G, Aijaz Fizza, Li Petvy, Sania Tanjina, Matsui Hiroshi, Awah Chidiebere U
UTR Therapeutics Inc., New York, NY, United States.
Department of Chemistry, Hunter College, City University of New York, New York, NY, United States.
Front Pharmacol. 2025 Aug 29;16:1630476. doi: 10.3389/fphar.2025.1630476. eCollection 2025.
Pancreatic ductal carcinoma is the most common and deadly form of pancreatic cancer, with an 11% survival rate. There is currently no cure. The first-line, mainstay therapy for pancreatic cancer is gemcitabine, capecitabine, or FOLFIRINOX. After 21 months, the chemoresistance begins, driven by the oncogenic c-MYC signal. This is a significant clinical and cancer biology challenge. The c-MYC oncogene has been shown to be overexpressed in primary (43.1%) and metastatic (31.6%) pancreatic cancers, respectively, and is the primary driver of the neoplastic changes and progression of pancreatic cancer metastasis. Here, we report the downregulation and inhibition of metastatic c-MYC-expressing lethal pancreatic cancer by the mRNA drug 3'UTRMYC1-18. The drug achieved on-target, c-MYC dose-dependent downregulation with complete pathological response, inhibition of liver, lung, and brain metastases with significant survival outcome, is safe, has a stable long half-life, and is well tolerated. Mechanistically, the therapeutic efficacy of the MYC-mRNA drug was achieved through downregulation of c-MYC-PD-L1.
胰腺导管癌是胰腺癌最常见且致命的形式，生存率为11%。目前尚无治愈方法。胰腺癌的一线主要治疗方法是吉西他滨、卡培他滨或FOLFIRINOX。21个月后，在致癌性c-MYC信号的驱动下开始出现化疗耐药。这是一个重大的临床和癌症生物学挑战。已证明c-MYC癌基因在原发性（43.1%）和转移性（31.6%）胰腺癌中分别过度表达，并且是胰腺癌转移的肿瘤性变化和进展的主要驱动因素。在此，我们报告了mRNA药物3'UTRMYC1-18对表达转移性c-MYC的致死性胰腺癌的下调和抑制作用。该药物实现了靶向、c-MYC剂量依赖性下调，伴有完全病理缓解，抑制肝、肺和脑转移，具有显著的生存结果，安全，半衰期长且稳定，耐受性良好。从机制上讲，MYC-mRNA药物的治疗效果是通过下调c-MYC-PD-L1实现的。
