MicroRNA Treatment for Pancreatic Cancer Shows Promise in Model

MicroRNAs (miRNAs) and short interfering RNAs (siRNA) comprise a class of about 20 nucleotides-long RNA fragments that block gene expression by attaching to molecules of messenger RNA in a fashion that prevents them from transmitting the protein synthesizing instructions they had received from the DNA. With their capacity to fine-tune protein expression via sequence-specific interactions, miRNAs help regulate cell maintenance and differentiation.

The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Investigators at Tel Aviv University (Israel) recently demonstrated the potential of a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors.

The investigators used proteomic-microRNA profiles and survival data of PDAC patients from The Cancer Genome Atlas (TCGA), to identify a novel signature for prolonged survival. Accordingly, they utilized a microRNA-mimic to increase miR-34a together with siRNA to silence the PLK1 (polo like kinase 1) oncogene.

The transport system incorporated a large globular supramolecular structure based on a polyglutamic acid (PGA) backbone for delivering miRNA and siRNA to tumors in vivo. Via the pendent free gamma-carboxyl group in each repeating unit of l-glutamic acid of the PGA, the investigators conjugated in parallel ethylenediamine and alkylamine moieties to form a positively charged amphiphilic nanocarrier. Utilizing electrostatic-based interactions, this cationic nanocarrier formed a polyplex with the negatively charged oligonucleotide cargo. The nanocarrier facilitated delivery of oligonucleotides by improving their stability in the bloodstream and enabling accumulation of the polyplex at the tumor site due to the enhanced permeability and retention (EPR) effect.

Results published in the January 2, 2017, online edition of the journal Nature Communications revealed that miRNA/siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of the MYC oncogene, a common target of both miR-34a and PLK1.

"Despite all the treatments afforded by modern medicine, some 75% of all pancreatic cancer patients die within 12 months of diagnosis, including many who die within just a few months," said senior author Dr. Ronit Satchi-Fainaro, professor of physiology and pharmacology at Tel Aviv University. "But around seven percent of those diagnosed will survive more than five years. We sought to examine what distinguishes the survivors from the rest of the patients. We thought that if we could understand how some people live several years with this most aggressive disease, we might be able to develop a new therapeutic strategy."

"We designed a nanocarrier to deliver two passengers: (1) miR-34a, which degrades hundreds of oncogenes; and (2) a PLK1 small interfering RNA (siRNA), that silences a single gene," said Dr. Satchi-Fainaro. "These were delivered directly to the tumor site to change the molecular signature of the cancer cells, rendering the tumor dormant or eradicating it altogether. The nanoparticle is like a taxi carrying two important passengers. Many oncology protocols are cocktails, but the drugs usually do not reach the tumor at the same time. But our "taxi" kept the "passengers" -- and the rest of the body -- safe the whole way, targeting only the tumor tissue. Once it "parked", an enzyme present in pancreatic cancer caused the carrier to biodegrade, allowing the therapeutic cargo to be released at the correct address -- the tumor cells."

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