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Grouped MicroRNAs Fight Glioblastomas

Glioblastoma cells.

MicroRNAs—strings of nucleotides that bind to and destroy messenger RNA to prevent the production of certain proteins—have been discovered to play an important role in cancer and other diseases. However, in previous preclinical trials, microRNA cancer treatments lacked efficacy.

In recent developments, scientists at Brigham and Women's Hospital and Harvard Medical School grouped micro-RNA molecules together, encoding them in a small, artificial gene, and then infiltrated cancer cells to overproduce the grouped microRNA molecules. The results of this study, published in Nature Communications, show promise: this treatment method increased survival in mice with glioblastoma.

"I like to think of it as hitchhiking. Cancer cells have a built-in system to produce and recognize microRNAs, and we're getting them to 'pick up' our sequence—which encodes multiple microRNAs—and start making more copies of them. The cellular machinery is running, and our sequence is along for the ride," remarked corresponding author Pierpaolo Peruzzi, MD, PhD, Assistant Professor of Neurosurgery at Harvard Medical School and Principal Investigator at the Harvey Cushing Neuro-Oncology Laboratories at Brigham and Women's Hospital.

The investigators discovered three microRNAs—miR-124, miR-128, and miR-137—that function together in healthy neurons but are missing during the formation of cancerous neurons. The three microRNAs target proteins implicated in glioblastoma recurrence and therapy resistance; without these microRNAs present, glioblastomas are able to thrive. When the researchers controlled all three microRNAs and used chemotherapy in mice with glioblastomas, mice survival was extended to 48.5 days. Without controlling all three microRNAs, mice whose glioblastomas remained untreated survived 12 days, and mice dosed with chemotherapy alone survived 18 days.

"These results are very encouraging and may provide a realistic treatment option," commented Vivek Bhaskaran, PhD, a postdoctoral fellow in the Department of Neurosurgery at Brigham and Women's Hospital.

When the three microRNAs are controlled by researchers, the tumors cells do not die; they only weaken. Dr. Peruzzi emphasized why this method is still beneficial in treating cancer: "While it seems a bit counterintuitive, this is actually an advantage, since by remaining alive although severely impaired, cancer cells continue to produce microRNAs which eventually flood the entire tumor."

"We're coaxing the tumor to produce its own poison, and then we hit it for good with chemotherapy or radiation," commented Dr. Peruzzi. "And we're optimistic that in a relatively short time, we can advance this approach to the clinic. A further refined and even more potent version of this concept is already in the pipeline."

For More Information

Bhaskaran V, Nowicki MO, Idriss M, et al (2019). The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma. Nat Commun, 10:442. DOI:10.1038/s41467-019-08390-z

Image courtesy of The Armed Forces Institute of Pathology

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