The Hitchhiker's Guide to Overcoming Glioblastoma

In cancer treatment research, microRNAs – tiny chains of nucleotides that form in cells – have been both a source of excitement and disappointment. Preclinical studies have shown that microRNAs play an important role in cancer and other diseases, but to date, two cancer clinical trials using microRNAs have shown poor response and significant toxicity. A team of investigators from Brigham and Women's Hospital and Harvard Medical School began examining these molecules in a totally new way. Rather than modulate one, they have grouped several micro-RNA naturally present in the brain by coding them in a small artificial gene, and have opted for the molecular machinery of cancer cells to overproduce these groups of molecules in order to weaken them. Their approach has shown promising results in preclinical models, increasing survival five times in a mouse model of glioblastoma when it was badociated with chemotherapy. The results of the team are published in Nature Communications.

"I like to think that it's hitchhiking. Cancer cells have an integrated system for producing and recognizing microRNAs and we have them capture our sequence – which codes for several microRNAs – and is starting to replicate others.The cell machinery is running and our sequence is long, "said Pierpaolo Peruzzi, MD, Ph.D., neurosurgeon clinician in the Department of Neurosurgery, and senior researcher at Harvey Cushing. Neuro -The Oncology Laboratories at Brigham.

Peruzzi and colleagues, including lead author Vivek Bhaskaran, Ph.D., a postdoctoral fellow in the department of neurosurgery, have begun to find microRNA groups responsible for complex pathway regulation. With the help of bioinformatic badyzes, the team focused on a group of three microRNAs – miR-124, miR-128 and miR-137 – that work as a team to develop properly. neurons but are lost during the formation of brain cancer. The team discovered that many of the targets of these microRNAs included proteins involved in recurrence of glioblastoma and resistance to conventional therapies.

The research team tested its findings using several cancer cell lines, including glioblastoma and non-glioblastoma cell lines. In addition, researchers tested the effectiveness of simultaneous modulation of all three microRNAs in a mouse model of intracranial tumors. The team reported a significant benefit for survival. Without treatment, the murine model survived 12 days after tumor implantation, and chemotherapy extended to a median of 18 days. But when chemotherapy and multi-microRNA treatment were combined, survival was prolonged to a median of 48.5 days.

"These results are very encouraging and can be a realistic treatment option," said Bhaskaran.

Peruzzi notes that the multi-microRNA strategy weakens tumor cells but does not kill them directly. "While this sounds a bit counterintuitive, it's actually an advantage because by staying alive, albeit severely impaired, the cancer cells continue to produce microRNAs that eventually flood the entire tumor." Indeed, the authors have shown that these artificial microRNAs propagate in the tumor through tiny vesicles and make it more vulnerable to chemotherapy.

"We are persuading the tumor to produce its own poison, and then we are definitely fighting it with chemotherapy or radiation therapy," Peruzzi said. "And we are optimistic that in a relatively short period of time we will be able to evolve this approach towards the clinic, and an even more refined and even more powerful version of this concept is already underway."

Brigham currently uses clinical trials using viral vectors and gene therapy approaches to treat glioblastoma (primary and recurrent). Peruzzi and colleagues are working to refine their microRNA approach to use viral vectors to deliver these microRNAs to tumors in patients with brain cancer.

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Brigham and Women's Hospital