Abstract 2592: Development of a novel modified miR-15a mimic with enhanced therapeutic potential for treatment of pancreatic ductal adenocarcinoma

Abstract

Abstract Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge associated with resistance and early recurrence. There is an urgent need to discover and develop new strategies to enhance treatment efficacy and improve prognosis for pancreatic cancer patients. microRNAs (miRNAs) play critical roles as oncogenes or tumor suppressors in the regulation of cancer development and progression. Our previous study identified miR-15a as a tumor suppressor miRNA and potential therapeutic candidate in PDAC. The expression of miR-15a is significantly down-regulated in PDAC compared to normal pancreas and is associated with proliferation and epithelial mesenchymal transition (EMT) through targeting genes such as BMI-1. In addition to BMI-1, we have identified Wee1, Chk1, and Yap-1 as direct targets of miR-15a in PDAC. We also analyzed the correlation between expression of miR-15a and its downstream target Cdc2 in PDAC clinical samples by real-time PCR and immunochemistry (IHC). Our results show that miR-15a expression is inversely correlated with Cdc2 expression in PDAC tissues and miR-15a expression is significantly associated with prognosis. To further explore the therapeutic potential of miR-15a in PDAC, we have designed a modified version of miR-15a, by replacing uracil residues in the guide strand of miR-15a with 5-Fluorouracil (5-FU). This modified miR-15a mimic combines the therapeutic powers of 5-FU and miR-15a. The miR-15a mimic has improved stability and efficacy compared to the native miR-15a. miR-15a mimic also retains target specificity for Wee1, Chk1, BMI-1 and Yap-1, and regulates the Wee1/Chk1-Cdc25c-Cdc2 signaling pathway. Another unique feature of this miR-15a mimic is that it can be delivered to cancer cells without the aid of a delivery vehicle. The miR-15a mimic has enhanced ability to inhibit the proliferation of a panel of pancreatic cancer cell lines compared to native miR-15a, with IC50 values of 18.713 nM and 37.541 nM respectively. miR-15a induces significant cell cycle arrest at the G1/S checkpoint and miR-15a mimic induces S phase arrest. In addition, we demonstrated that there is a synergistic effect by combining miR-15a mimic and gemcitabine in reducing pancreatic cancer cell proliferation, with reduced IC50 for both drugs. The therapeutic potential of miR-15a mimic was also demonstrated in vivo using a metastatic mouse pancreatic cancer model. miR-15a mimic (3.2 mg/kg) inhibits metastatic tumor growth at a dose that is 15-fold less than that of gemcitabine (50 mg/kg) and the inhibitory effect is enhanced in combination with gemcitabine. While mice treated with gemcitabine alone developed resistance, we did not observe any resistance in mice treated with miR-15a mimic. This study demonstrates that miR-15a mimic has great potential to be further developed as a novel therapeutic drug for treatment of PDAC. Citation Format: Shixiang Guo, Andrew Fesler, Wenjie Huang, Yunchao Wang, Jiali Yang, Xianxing Wang, Ga-Ram Hwang, Matthew Godwin, Huaizhi Wang, Jingfang Ju. Development of a novel modified miR-15a mimic with enhanced therapeutic potential for treatment of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2592.