Abstract
Abstract Pancreatic cancer, including its most common subtype, pancreatic adenocarcinoma (PDAC), has the lowest five-year survival rate among patients with PDAC in the United States. Despite advancements in anticancer treatment, the overall median survival for patients with PDAC has not dramatically improved. Therefore, there is an urgent need to develop new strategies of treatment to address this issue. Non-coding RNAs, including microRNAs (miRNAs), have been found to have major roles in carcinogenesis and the subsequent treatment of various cancer types like PDAC. In this study, we developed a new treatment strategy by modifying tumor suppressor miRNAs, hsa-miRNA-15a (miR-15a) with the nucleoside analog chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics of miR-15a (Gem-miR-15a). In a panel of PDAC cell lines, we found that Gem-miR-15a induces cell cycle arrest and apoptosis, and these mimics are potent inhibitors with single digit nM IC50 up to several hundred fold less than their native counterparts or Gem alone. Furthermore, we found that Gem-miR-15a retained miRNA function by downregulating the expression of several key targets including WEE1, CHK1, BMI1, and YAP1 for Gem-miR-15a. Compared to Gem, we also found that our Gem-modified miRNA mimics exhibit enhanced efficacy by over several hundred fold less than Gem in patient-derived PDAC organoids. Gem-miR-15a was able to eliminate Gem resistant PDAC cells and organoids. In addition, Gem-miR-15a was able to be delivered to PDAC cells without the aid of delivery vehicle, a major advancement in nucleic acid based medicine. Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth in vivo without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of muti-targeted Gem-modified miRNAs as a novel treatment strategy for PDAC. Citation Format: Jingfang Ju. Development of novel gemcitabine-modified miRNA mimics for pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B076.
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