Background

Resistance to chemotherapy can be a highly complex issue, with epigenetic alterations playing a key role in tumorigenesis and chemotherapy resistance. The failure to treat several advanced solid tumors can be often attributed to resistance to fluoropyrimidine-based and gemcitabine chemotherapy. One form of epigenetic alteration includes changes in expression of non-coding RNAs. Non-coding RNAs, such as microRNAs (miRNAs), have been found to regulate several key targets that are responsible for cancer stemness, and function as oncogenic miRNAs or tumor suppressor miRNAs. In particular, miR-15a is one of the major tumor suppressor miRNAs that is either lost or has reduced expression in many cancer types. Thus, restoration or miR-15a poses a potential strategy for suppressing multiple oncogenic targets.

Technology

Dr. Jingfang Ju and his team have developed a platform for modifying miRNAs and using the modified miRNAs as novel cancer therapeutics. The unique design of the miRNAs enhances the stability, therapeutic efficacy, and ease of delivery. The miRNA modification platform replaces the uracil and cytidine bases with anticancer nucleoside analogs, such as the chemotherapeutic drugs 5-Fluorouracil (5-FU) and gemcitabine (Gem). The miRNAs are further modified by also integrating methotrexate (MTX). As an example, Dr. Ju designed and synthesized MTX-5-FU-Gem-miR-15a. The rationale behind this design is that folate receptor/reduce folate carrier, which is elevated in cancer cells, will be used to improve tumor specificity. MTX, once broken down from the miRNA memetic, will add to the tumor killing effect of the modified miRNA tumor suppressor.

Advantages

Delivered to cancer cells with no transfection reagent – More potent inhibitors of cell proliferation – Enhanced stability