Glioblastoma Treatment: New Promising Developments

Cancer is one of the top leading causes of mortality globally. The growing prevalence of the disease has to do with both our changing environment and longer lifespan. It is said that if all humans lived for 200 years, most people would develop cancer at some time in life. Thus, finding a cure for cancer is vital for longevity

Cancer is the unregulated growth of one or another type of cells. In the case of glioblastoma, it is the unchecked growth of glial cells in the brain. Fortunately, brain cancers are less common in comparison than those found in other parts of the body. However, when they occur, they are difficult to treat.

Glial cells are a group of cells that have varied functions in the brain. In the past, they were thought to merely be glue cells that help to keep neurons at the place. But now it is understood that glial cells have many other functions, and help to maintain brain health. They do the cleaning, repair, and maintenance, and also play a role in the local immunity.

A glioblastoma is a rare form of cancer—its occurrence is about 10 in 100,000. Among the brain cancers, however, glioblastomas account for 15% of all cases. It is one of the most aggressive types of brain cancers. Thus, even with the best of treatment, most patients will barely survive one and a half years. Very small numbers of patients can expect to live longer than three years, and less than 5% live up to 5 years.

Despite the progress in the treatment and management of other forms of cancer, only a few positive glioblastoma treatment developments were reported in the last decades. For more than half a century, treatment of brain cancers remains based on surgery and chemotherapy. Usually, the surgeon would remove the affected part of the brain, and then they would try to suppress the remaining cancer cell with highly toxic chemotherapeutic agents. This approach has not been working well for glioblastoma.

These days, thanks to advancements in personalized medicine and a better understanding of cellular physiology and genetics, newer cancer treatments are being developed. Instead of mere surgical removal or the use of toxic drugs, researchers are learning ways to control various cellular mechanisms. Using these novel methods, it is possible now to force the brain tumor into remission or train the brain’s immune system to work against cancer.

Exploiting what forces cancer into remission

Genes and various factors control every part of cellular life. Thus, cells grow in a particular fashion, behave in a specific way and, when required, go through programmed cell death. In the case of glial cells, this programmed cell death is called anoikis. Further, to keep the brain functioning, these supportive cells also engage in autophagy. Autophagy is a process that helps to keep the brain clear of debris and unnecessary components.

Autophagy can be both protective and dangerous to brain cells. Autophagy helps cancerous glioma stem cells resist anoikis. Autophagy is now known to be regulated by the MDA-9/Syntenin gene. Researchers have found that when the MDA-9/Syntenin gene is blocked, the glioma stem cells lose their protective ability and succumb to programmed death (i.e., anoikis).

Further, researchers found that MDA-9/Syntenin gene suppresses epidermal growth factor receptor (EGFR) signaling. Excessive EGFR signaling has been found to be associated with brain cancer/glioblastoma. EGFR is protective against excessive autophagy or programmed cell death.

Scientists realized that when the MDA-9/Syntenin gene is blocked, EGFR cannot regulate protective autophagy, and more widespread death of cancer cells ensues. Now, researchers want to use this feature in a controlled manner to kill the cancer cells.

At present, this approach is being tested in laboratory models of tumor cells and in mouse models. Initial results seem to be encouraging. Suppression of the MDA-9/Syntenin gene in mouse models led to higher survival rates.

Researchers are confident that in the near future they will be able to find safer ways to suppress the MDA-9/Syntenin gene in humans and then start trials on people diagnosed with glioblastoma.

Training immune system to destroy cancer cells

This is another approach towards the treatment of various types of cancers. Clinical research has already shown the efficacy of this approach in glioblastoma and many other types of cancers. This approach involves creating an individualized or personal vaccine for each patient with glioblastoma. The initial human trials have already shown a better survival rate.

When it comes to creating a vaccine against cancer, one size does not fit all. The reason is simple; each cancer patient differs genetically. This difference in each cancer patient is linked to the fact that cancers develop due to different mutations across individuals. It means that all patients with glioblastoma have slightly different types of tumor. Therefore, one single vaccine would not work.

The answer to these patient-specific cancerous mutations is a personalized vaccine. This vaccine is called DCVax-L. The vaccine is created by extracting cancer cells from individuals and then training the dendritic cells of the immune system to fight against those specific mutations or cancer cells. Each patient who gets this vaccine would first go through the traditional surgical and chemotherapeutic treatments.  Upon completion of these treatments, the patients would receive the vaccines created specifically for them, to prolong life.

Good news is that this method is already in the last stages of development, and it has shown excellent results in a randomized, blind clinical trial. In these trials, the DCVax-L vaccine was given to 232 patients at various sites. This trial has not yet ended, but the initial results clearly show the higher survival rate. Around 30% of those who got this vaccine survived more than 30 months, and one-fourth survived more than 36 months. At present, 32.6% of those enrolled in the trial are still alive, and they are expected to live between 46.5 to 88.2 months. At present, the vaccine is not a curative treatment, but it provides serious benefits in comparison to traditional methods.

It has taken more than two decades to perfect the vaccine, and researchers believe that things will only get better in the future. In the very near future, we can expect to see much higher 5-year survival rates for glioblastoma patients, and that would already mark a big success.

References

D’Agostino, P. M., Gottfried-Blackmore, A., Anandasabapathy, N., & Bulloch, K. (2012). Brain dendritic cells: biology and pathology. Acta Neuropathologica, 124(5), 599–614. https://doi.org/10.1007/s00401-012-1018-0

Hanif, F., Muzaffar, K., Perveen, K., Malhi, S. M., & Simjee, S. U. (2017). Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment. Asian Pacific Journal of Cancer Prevention?: APJCP, 18(1), 3–9. https://doi.org/10.22034/APJCP.2017.18.1.3

Jäkel, S., & Dimou, L. (2017). Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation. Frontiers in Cellular Neuroscience, 11. https://doi.org/10.3389/fncel.2017.00024

Liau, L. M., Ashkan, K., Tran, D. D., Campian, J. L., Trusheim, J. E., Cobbs, C. S., … Bosch, M. L. (2018). First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. Journal of Translational Medicine, 16, 142. https://doi.org/10.1186/s12967-018-1507-6

Talukdar, S., Pradhan, A. K., Bhoopathi, P., Shen, X.-N., August, L. A., Windle, J. J., … Fisher, P. B. (2018). MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells. Proceedings of the National Academy of Sciences, 115(22), 5768–5773. https://doi.org/10.1073/pnas.1721650115

Walid, M. S. (2008). Prognostic Factors for Long-Term Survival after Glioblastoma. The Permanente Journal, 12(4), 45–48. PMID: 21339920

Image via VSRao/Pixabay.

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