# Development of novel miRNA based novel therapeutics for metastatic colorectal cancer

> **NIH VA I01** · NORTHPORT VA MEDICAL CENTER · 2022 · —

## Abstract

Project Summary/Abstract The goal of this application is to investigate the roles of miR-15a in colorectal
cancer and to develop novel miR-15a mimic as potential therapeutics to treat advanced metastatic colorectal
cancer in both male and female Veterans. Despite advancements in early detection and improved treatment
strategies, there are still 50,260 deaths due to colorectal cancer in the United States, and its incidence is
equally high in the Veteran population. Resistance to fluoropyrimidine-based chemotherapy is one of the major
causes for the failure of treating advanced metastatic colorectal cancer. It has been recognized recently that
epigenetic alterations play a key role in tumorigenesis and resistance to 5-fluorouracil (5-FU) based
chemotherapy. Because colorectal cancer cells are highly heterogeneous, chemotherapy can be quite effective
in eliminating most of the rapid proliferating cancer cells. However, a small population of slow proliferating
cancer stem cells are highly resistant which leads to cancer recurrence. Although the mechanism of
chemoresistance is complex and is often associated with elevated target enzyme thymidylate synthase (TS,
TYMS), recent studies from our laboratory have shown that epigenetic alterations such as changes in
expression of non-coding miRNAs are major contributors to such resistance mechanisms to 5-FU by providing
acute changes in protein synthesis at the post-transcriptional and translational levels. miRNAs are a class of
small non-coding RNAs with crucial regulatory functions. We have identified a number of miRNAs with tumor
suppressive functions in colorectal cancer. In particular, we have demonstrated that miR-15a (hsa-miR-15a-5p)
can overcome chemoresistance in colorectal cancer as a potent tumor suppressor by inhibiting the expression
of several major therapeutic target genes (BMI1, BCL2, YAP1, DCLK1) and associated pathways. More
importantly, we have recently developed a novel strategy to create modified miRNA mimics with enhanced
stability and efficacy for eliminating 5-FU resistant colon cancer stem cells while retaining target specificity.
miR-15a mimics were designed by modifying the target strand of miR-15a by replacing uracil (U) bases with 5-
FU at various locations. The rationale behind this approach is that 5-FU modification of miR-15a will enhance
stability, and also combining the power of 5-FU and multi-targeted miR-15a into one entity to create therapeutic
synergy, as miR-15a will breakdown eventually to release 5-FU. A unique feature of the 5-FU modified miR-
15a is that it can be internalized by colon cancer cells without any delivery vehicle. This represents a major
advancement and a paradigm shift in miRNA based therapeutic development. Our preliminary results show
that such modification improves the potency and stability of the miR-15a mimic and enhances its ability to
inhibit colon cancer metastasis in vivo without any observed toxicity. Specific Aim 1: We will define the direc...

## Key facts

- **NIH application ID:** 10256956
- **Project number:** 1I01BX005260-01A1
- **Recipient organization:** NORTHPORT VA MEDICAL CENTER
- **Principal Investigator:** JINGFANG JU
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10256956

## Citation

> US National Institutes of Health, RePORTER application 10256956, Development of novel miRNA based novel therapeutics for metastatic colorectal cancer (1I01BX005260-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10256956. Licensed CC0.

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