New peptide therapy shows promise against glioblastoma recurrence

A lab-designed molecule developed and extensively studied by scientists with Virginia Tech's Fralin Biomedical Research Institute at VTC could represent a breakthrough in slowing tumor recurrence in glioblastoma, an aggressive and deadly form of brain cancer.

In a study published in May in Cell Death and Disease, researchers identified a previously unknown trait of cancer cells that shows promise for therapeutic intervention. The group outlined the mechanism of action and effectiveness of the experimental drug known as JM2, revealing its potential as a peptide therapy to target cancer cells that can renew and regrow, even after chemotherapy and radiation.

Glioblastoma, the most common form of malignant brain tumor, is particularly difficult to treat. The median survival after diagnosis is just over 14 months. 

Treatment typically involves surgically removing as much of the tumor as possible, followed by radiation and chemotherapy with a drug called temozolomide. However, glioblastoma always recurs due to the presence of treatment-resistant glioblastoma stem cells. These cancer cells can survive, even after standard therapies, leading to tumor regrowth.

Glioblastoma stem cells can adapt easily to both their environment and treatment. These cells can lie dormant, and at some point, they reawaken and then rebuild the tumor. It's critical to find a way to target this population of cancer cells."

Samy Lamouille, corresponding author of the study and assistant professor at the Fralin Biomedical Research Institute

The Lamouille lab studies how cancer cells communicate with each other and with their surrounding environment, with a particular focus on connexin 43. That protein plays a key role in forming gap junctions, which enable direct cell-to-cell communication.

"Connexin 43 plays a complex role in cancer," Lamouille said. "Depending on its expression and localization in cancer cells, it can both suppress and support cancer growth." 

Experimenting with laboratory-grown glioblastoma stem-like cells, Lamouille turned to super-resolution microscopy, a powerful technique that allows researchers to visualize and localize proteins at nanoscale.

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

Building on this discovery, Lamouille came up with the idea to use JM2, a connexin 43-derived peptide that mimics the microtubule-interacting domain of connexin 43, to further explore its role in glioblastoma stem cells. 

Rob Gourdie, the Heywood Fralin professor at the Fralin Biomedical Research Institute, developed the JM2 peptide with his laboratory while at the Medical University of South Carolina. 

"When we tested JM2 in glioblastoma stem-like cells, that was the most exciting moment," Lamouille said. "Not only did that efficiently disrupt connexin 43 interaction with microtubules, but JM2 was also toxic specifically for these particular cells, leaving healthy brain cells unharmed."

It achieved the effect without affecting connexin 43's other crucial functions. 

Beyond glioblastoma, the work represents a significant step toward identifying a novel tumorigenic function for connexin 43.

"I can remember presentations by the team in which the three-dimensional gliospheres used to model tumors in the culture dish were clearly getting smaller," said co-author Gourdie. "It was surprising to see such a drastic effect on glioblastoma. The JM2 peptide had a killing effect by itself. That was unexpected."

Through further testing in both cell cultures and living organisms, the researchers found that JM2 disrupts the maintenance of these treatment-resistant cancer cells in laboratory experiments and significantly slows tumor growth in animal models. These findings support JM2 as a promising new peptide-based drug for targeting the glioblastoma stem cells that drive tumor recurrence following treatment.

The research also highlights the partnership between Virginia Tech's Fralin Biomedical Research Institute and Carilion Clinic, a health system in Southwest Virginia.

Co-author Michael Lunski was a Carilion Clinic resident who conducted research in Lamouille's laboratory, which is adjacent to that of Assistant Professor Zhi Sheng. Sheng provided glioblastoma cells that helped lead to the discovery; these lab cultures were derived from tumor cells donated with the consent of brain cancer patients in Southwest Virginia receiving care from Carilion physicians.

While more research is needed to develop the therapy for use and determine whether it will be safe and effective in humans, preclinical findings suggest that combining JM2 with chemotherapy could improve patients' survival by slowing recurrence.

To advance the approach, Lamouille is now experimenting with novel delivery 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 licensed the JM2 peptide in an effort to bring new therapies to cancer patients.