Nobody wants to hear a cancer diagnosis, especially not a prognosis of glioblastoma, a deadly variant of brain cancer where patients typically survive only 15 months following diagnosis.
But what makes glioblastoma so deadly? A separate study conducted three years ago discovered that this aggressive brain tumor grows by turning normal brain cells (i.e. neurons) into stem cells that can constantly replicate and make a new tumor. This, in turn, makes normal cancer treatments such as chemotherapy and surgery very difficult, as physicians have not developed a universal method of “cleansing” the brain of all cells.
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Although there is no current cure to the disease today, pioneering research from UCSD has developed a new computational strategy to search for molecules that could be developed into glioblastoma drugs.
Prior to human trials, research was first conducted on mice. In these trials, it was discovered that one molecule shrank the average tumor in half. In order for glioblastoma to survive and metastasize, two proteins that were transcription factors have to bind together. However, this new molecule inhibits this binding, leading to an inability for the glioblastoma to survive and develop, a feat that most experts thought was impossible.
In order to understand the deep significance of this inhibition, however, it is crucial to first comprehend what transcription factors are. Transcription factors are proteins that regulate the activity of particular genes. In healthy individuals, these proteins labor ceaselessly in an orchestrated system. In glioblastoma, however, one misfiring transcription factor named OLIG2 keeps cell growth and survival genes “active” when they should not be, spurring fast-growing tumors.
Now that we understand what transcription factors do, let’s concentrate on the study. In order to function properly, transcription factors must “buddy up” and bind to another transcription factor while simultaneously binding to DNA. If you’re a bit confused by all of this terminology, a simpler way to look at this idea is to picture a sandwich. The transcription factors can be seen as the bread, and the meat of the sandwich can be likened to the DNA component of our system. Thus, just as two a sandwich is comprised of two loaves of bread that surround meat, this system can be looked at as two transcription factors “sandwiching” DNA. If any of these associations are interrupted, the transcription factors are inhibited.
Utilizing this approach, Dr. Tsigelny and his team aimed to disrupt this “buddy linkage” in the OLIG2 transcription factor. Based on the known structures of similar transcription factors, Valentina Kouznetsova constructed a computational strategy to search databases of 3D molecular structures for those small molecules that might engage with the hotspot between two OLIG2 transcription factors and disrupt them. This newfound molecule, through the act of attaching to the OLIG2 trans factor, ends up disrupting their function.
Through this method, the researchers identified several molecules that would likely fit the OLIG2 interaction, and then tested them. The most effective of these was found to be SKOG102, which shrank human glioblastoma tumors grown in mouse models by around 50%.
According to Kesari, although the initial pre-clinical findings are promising, it will be several years before a type of therapy such as this can be tested in humans. Despite this, this study is a model for the increasing amount of computational applications of medicine.
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