Scientists find promising in a new peptide drug to fight against fatal brain cancer

A molecule designed in the laboratory has developed and widely studied by scientists with the Fratin Biomedical Institute of Virginia Tech in VTC could represent a breakthrough in the slowdown in tumor recurrence in glioblastoma, an aggressive and fatal form of brain cancer.

In a study published in Death and cell diseaseThe researchers have identified a line previously unknown to cancer cells which are promising for therapeutic intervention. The group has described the mechanism of action and the effectiveness of the experimental drug known as JM2, revealing its potential as peptide therapy to target cancer cells which can be renewed and reproduced, even after chemotherapy and radiotherapy.

The glioblastoma, the most common form of malignant cerebral tumor, is particularly difficult to treat. Median survival after the diagnosis is just over 14 months old.

Treatment is generally to surgically eliminate as many tumors as possible, followed by radiotherapy and chemotherapy with a medication called Témozolomide. However, glioblastoma is still reproduced due to the presence of bloodstage -resistant glioblastoma cells. These cancer cells can survive, even after standard therapies, leading to tumor regrowth.

“Glioblastoma stem cells can easily adapt to their environment and treatment,” said Samy Lamouille, corresponding author of the study and assistant professor at the Biomedical Research Institute.

“These cells can be dormant, and at some point, they woke up and then rebuild the tumor. It is essential to find a means of targeting this population of cancer cells.”

The Lamouille laboratory studies how cancer cells communicate with each other and with their surrounding environment, with a particular accent on the Connexin 43. This protein plays a key role in the formation of gap junctions, which allow direct cell cell communication.

“Connexin 43 plays a complex role in cancer,” said Lamouille. “Depending on its expression and location in cancer cells, it can both remove and support cancer growth.”

Experimenting cells such as glioblastoma cultivated in laboratory, Lamouille has turned into super-resolution microscopy, a powerful technique that allows researchers to view and locate proteins on a nanometric scale.

The Associate Professor James Smyth specializes in this technique to study lacunar junctions and Connexin proteins in heart disease. Together, they discovered for the first time that the Connexin 43 is strongly associated with the microtubules of these cells, decorating them over their entire length.

Building on this discovery, Lamouille had the idea of ​​using JM2, a Peptide derived from Connexin 43 which imitates the interaction domain of microtubules of Connexin 43, to further explore its role in the stem cells of glioblastoma.

Rob Gourdie, the professor of Heywood Fralin at the Fratin Biomedical Research Institute, developed the Peptide JM2 with his laboratory when he was at the Medical University of South Carolina.

“When we tested JM2 in cells of the Glioblastoma rod type, it was the most exciting moment,” said Lamouille. “Not only did it effectively disturb the 43 connection interaction with microtubules, but JM2 was also toxic specifically for these specific cells, leaving unhappy healthy brain cells.”

He made the effect without affecting the other crucial functions of Connexin 43.

Beyond the glioblastoma, the work represents a significant step towards the identification of a new tumorigen function for the Connexin 43.

“I remember the presentations of the team in which the three-dimensional gliospheres used to model the tumors in the culture dish became clearly smaller,” said the co-author Gourdie. “It was surprising to see such a radical effect on the glioblastoma. The JM2 peptide had a killing effect by itself. It was unexpected.”

Thanks to other tests in cell cultures and living organisms, the researchers have found that JM2 disrupts the maintenance of these cancer cells resistant to treatment in laboratory experiments and considerably slows tumor growth of animal models. These results support JM2 as a new promising drug based on peptides to target the stem cells of glioblastoma which stimulate tumor recurrence after treatment.

Research also highlights the partnership between the Fratin Biomedical Institute of Virginia Tech and Crorical Callion Clinic, a health system in the southwest of Virginia.

The co-author Michael Lunski was a resident of the Callion Clinic who conducted research in the laboratory of Lamouille, who is adjacent to that of assistant teacher Zhi Sheng.

Sheng provided glioblastoma cells that helped lead to discovery; These laboratory crops have been derived from tumor cells given with the consent of patients with brain cancer in the southwest of Virginia receiving care from chilled doctors.

Although more research is necessary to develop therapy for use and determine whether it will be safe and effective in humans, preclinical results suggest that the combination of JM2 with chemotherapy could improve patient survival by slowing recidivism.

To advance the approach, Lamouille is now experimenting with new administration mechanisms specifically targeting the JM2 peptide to glioblastoma cells, including biodegradable nanoparticles and viral vectors.

Lamouille and Gourdie are co-founders of Acomhal Research Inc., which authorized the JM2 peptide in order to bring new therapies to cancer patients.