The Key to Unlocking Future Treatments for Brain Tumors

Ayah blog post picture — A molecule (key; yellow arrow) bound to the binding site of the appropriate fitting protein (lock).

In Canada, it is estimated that approximately 3000 people will be diagnosed with brain cancer this year¹. Glioblastomas (also known as glioblastoma multiforme) are one of the most common and aggressive forms of brain tumors that form from star-shaped cells in the brain called astrocytes. These tumors can reproduce at very fast rates and invade other nearby cells². As a result, glioblastomas are often ‘resistant’ to conventional treatments such as radio- and chemo-therapy, meaning that these tumors survive despite patients undergoing treatment. Unfortunately, this implies that survival rates remain relatively low. In fact, the 5 year overall survival rate for brain cancer is only 25%.¹ Despite this medical prognosis, advances in cancer research are allowing scientists to gain a better understanding of the genetic and cell pathways causing brain cancer development, which may ultimately lead to new treatment strategies.

For example, in 2009, a study conducted at Columbia University found that two proteins – C/EBP and STAT3 – are active in approximately 60% of glioblastoma patients. When activated together, C/EBP and STAT3 “turn on” hundreds of genes that then go on to transform normal brain cells into aggressive cancer cells. Researchers discovered that when they “turned off” C/EBP and STAT3 in human glioblastoma cells, and then injected them into mice, tumor formation was completely blocked³.

The identification of C/EBP and STAT3 as 2 potentially major players in the formation of glioblastoma provided insight into the key mechanisms involved in transforming ordinary brain cells into glioblastoma cells. This finding presented a novel approach to therapy that had never before been implicated in brain cancer and led other researchers to question whether new drugs could be developed to block C/EBP and STAT3 activity as a form of treatment.

The laboratory of Dr Patrick Gunning, a researcher at the University of Toronto (Mississauga campus) took on this challenge. The research team tried to create drugs that specifically target STAT3. Their work focuses on creating new molecules that bind to STAT3 and prevent it from functioning, as a way to try and block the progression of brain tumours. However, designing these molecules is not an easy task. Proteins are very complex; each has a unique structure and function. It is useful to think of this design process as a key and lock analogy. The goal in drug design is to create a molecule or drug (the “key”) that will only bind to a particular part of a protein (“the lock”). As a result, researchers must ensure that the molecule (or key) they create specifically fits the lock (protein) and not other proteins found in the body.

The Gunning lab was able to develop a drug they referred to as compound 31 (or SH-4-54), which was able to significantly disturb the function of the STAT3⁴. In other words, they found a promising key to fit into their specific “lock” of interest. When they injected compound 31 into mice that had glioblastoma tumor cells, the mice showed a decrease in STAT3 activity and a drop in the number of glioblastoma tumor cells. Their research concludes that this was likely due to the STAT3 protein’s reduced ability to “turn on” genes that may potentially contribute to tumor formation. Although further advancements need to be made to allow us to better understand the impact this potential new drug has on tumor cells, this research brings us one step closer in the development of new drugs for this disease. It also highlights the amount of research that is needed to go from “bench to bedside”. Science is continually discovering more about the biology of cancer, such as glioblastoma, and how these cancers develop. However, a significant amount of time and effort also goes into the development of drugs that are precise and are able to successfully target and stop the growth of cancer cells.

This article was written by Ayah Abdeldayem. She is a second year undergraduate student at the University of Toronto Mississauga pursuing a double major in Biology for Health Science and Chemistry. To learn more about Ayah and her passion for science check out our members page.

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