Abstract 5443: Developing a novel miR-15a mimic as a potential therapeutic molecule to eliminate resistant colorectal cancer stem cells

Abstract

Abstract In the last 15 years, it has become well established that microRNA play important roles in cancer biology. Due to their ability to regulate the expression of important target genes, aberrant expression of miRNAs has been linked to cancer development and progression. Based on these important functions, there is great interest in developing miRNA based therapeutics. In colorectal cancer, treatment using 5-flurouracil (5-FU) based chemotherapy has improved patient outcomes. However, there remain challenges associated with chemoresistance and recurrence for patients with advanced stage colorectal cancer. miRNA based therapeutics may represent an potential novel therapeutic option for colorectal cancer therapy either alone or in combination with 5-FU based chemotherapy. miR-15a was of the first miRNAs identified to be associated with cancer, and has been shown to have important roles in several tumor types. miR-15a is downregulated in colon cancer and associated with poor patient prognosis. We have identified several important cancer related targets of miR-15a in colon cancer, including YAP1, DCLK1, BMI1 and BCL2. Through the regulation of these targets, miR-15a expression can be used as a potent inhibitor to reduce colon cancer cell proliferation, invasion and improve sensitivity to 5-FU, as well as decreasing tumor growth in vivo mouse colon tumor models using colon cancer stem cells. In the interest of developing miR-15a based colon cancer therapeutics, we have made a modified miR-15a mimic that shows enhanced abilities to disrupt resistant colon cancer cell proliferation and induction of cell cycle arrest when compared to unmodified miR-15a. Following transfection with miR-15a mimic, cell number was reduced by 84% compared to control and 66% compared to miR-15a precursor. Cell cycle analysis showed that G1/S ratio was increased from 1.07 for control to 2.87 for precursor miR-15a and 7.07 for miR-15a mimic. This miR-15a mimic also maintains its ability to regulate these important target genes in colon cancer stem cells. In mouse models using colon cancer stem cells, miR-15a mimic has demonstrated therapeutic potential by reducing tumor growth. Based on these findings, there is potential that modified miR-15a could be adapted for treatment of patients to improve survival of advanced stage colorectal cancer patients. Citation Format: Andrew T. Fesler, Hua Liu, Ning Wu, Jingfang Ju. Developing a novel miR-15a mimic as a potential therapeutic molecule to eliminate resistant colorectal cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5443. doi:10.1158/1538-7445.AM2017-5443