Finding new ways to treat glioblastoma

In January 2022, Hans-Georg Wirsching and his research group started their  project, “A phase Ib/II randomized drug repurposing trial of glutamate signaling inhibitors in combination with chemoradiotherapy in patients with newly diagnosed glioblastoma (GLUGLIO)”, which was granted by the SNSF “Investigator-Initiated Clinical Trials (IICT)” funding scheme. This project aims to use anti-glutamatergic drugs to improve the standard treatment of patients who suffer from glioblastoma. This is the most common malignant primary brain tumor in adults and one of the deadliest types of cancer overall. With the randomized clinical trial, the researchers seek to bridge the emerging primary research field of “cancer neuroscience” and the clinical repurposing of already available anti-glutamatergic drugs to benefit glioblastoma patients.

Hans-Georg, congratulations on your research grant. What are the main goals of your project?
The overarching goal of this approach is to prolong patient survival and better understand the role of glutamate in glioblastoma biology. You know, the disease course of glioblastoma is invariably fatal despite intensive treatment by surgery and chemoradiotherapy.

How do you want to reach this goal?
In this clinical trial, a combination of three drugs, all inhibiting glutamate, will be given in addition to standard chemoradiotherapy: gabapentin, which inhibits glutamate synthesis, sulfasalazine, which inhibits its secretion and memantine, inhibiting glutamate signaling.

What was your motivation to start the project?    
As a physician-scientist, I almost daily experience the frustration of glioblastoma patients and their relatives over the limited efficacy of treatments. Therefore, the perspective of more effective therapies is a major driving force and motivation for my research.

So, how did the idea for the clinical trial emerge?
Our clinical analyses suggest that glioblastoma patients with enhanced neuronal excitability – related to glutamate activity – have a lower chance of survival. Thus, the idea for this clinical trial was born.

What challenges did you have to face during the project?
The greatest challenge was establishing a network of idealistic and enthusiastic investigators and study teams in eight clinical centers throughout Switzerland who believed in this clinical trial. Recruiting enough glioblastoma patients to obtain meaningful results requires such a network. Moreover, clinical trials are costly, so even generous funding through an SNSF IICT grant can only cover the cost of some involved personnel.

What is the project’s significance or impact on society and medicine?
The GLUGLIO trial studies clinically approved drugs that are typically prescribed for other conditions – gabapentin for epilepsy, sulfasalazine for inflammatory bowel diseases, and memantine for Alzheimer’s. Safety profiles of all three drugs are well established, and patents have long expired. Therefore, the drug repurposing concept of this trial exemplifies a straightforward way to develop new, cost-effective therapies. This approach is of particular importance in the light of limited resources.

Thank you for these insights! Is there anything else about the project you would like to tell us?
Yes, there is. The extensive resources needed to conduct a clinical trial require that we learn as much as possible. Therefore, a whole battery of assessments will be done in the GLUGLIO trial, including molecular analyses of tumor tissues, serial electroencephalography, magnetic resonance imaging, and tumor spectroscopy. In addition, assessments of neurocognition, epilepsy, and quality of life. All this would be impossible without the exceptional effort of many professionals, our patients, and their relatives.

Useful links
Hans-Georg Wirsching’s website
Article that summarizes the most important literature on cancer neuroscience

Image: Gerd Altmann, Pixabay