INTRODUCTION TO GLIOBLASTOMA
Cancer Overview
To understand GBM, we must first understand the basics of cancer. At its most basic level, cancer is uncontrolled proliferation of cells. This occurs usually due to a DNA level change that inhibits normal regulators of growth. There are 8 hallmarks traditionally associated with cancer cells, that are traditionally used to different cancer versus non-cancer cells. These include ways to continue growing, such as sustaining proliferative signaling, enabling DNA replication, avoiding cell death, and avoiding suppressors of growth. They also include ways to avoiding immune cells that may detect the cancer and inducing changes to make the environment more favorable by creating new blood vessels and generating tumor-promoting inflammation. (Figure 1).
![Figure 1: Hallmarks of Cancer [1]](https://images.squarespace-cdn.com/content/v1/5eb33415103cec086b318132/1589148452737-Q8531CKGQF2D3L6TMMSS/hallmarksbetter.jpg)
Figure 1: Hallmarks of Cancer [1]
Together, these factors create an environment where cells can proliferate uncontrollably, thus creating a tumor (Figure 2). This tumor will continue to grow and will eventually end up compressing structures around it, which is what creates the symptoms patients experience. For example, with brain tumors, compression of other brain structures will create symptoms like dizziness, headaches, etc. In addition, depending on the tumor, it may eventually invade the blood vessels and metastasize to other organs, creating additional symptoms and making it increasingly difficult to eradicate.
![Figure 2: Uncontrolled Proliferation of Cells [2]](https://images.squarespace-cdn.com/content/v1/5eb33415103cec086b318132/1589148997668-6VRWF5K8M606PGMSWBAI/proliferation.gif)
Figure 2: Uncontrolled Proliferation of Cells [2]
GBM Overview
Glioblastoma (GBM) is a type of cancer that occurs in the brain. It is the most common primary malignant tumor in adults, accounting for ~52% of all brain tumors [3]. GBM is derived from glial cells (oligodendrocytes and astrocytes) in the brain, which are common nerve support cells, It is defined as a Grade IV tumor by the WHO scale, putting it in the class of the most aggressive brain tumors. However, notably, although it is highly invasive within the brain, GBM does not typically metastasize to other organs.
After diagnosis with GBM, the current standard of care involves maximal surgical resection, followed by temozolomide-based chemotherapy, radiation, and tumor-treating fields. However, even with these measures, the tumor inevitably recurs in 100% of patients. This recurrent tumor is always fatal, with a median survival of about 21 months based on the most recent studies [4] (Figure 3). Our goal is to research ways to address the primary or recurrent tumor in order to improve outcomes for patients.
Figure 3: Current Standard of Care for GBM
A Video Review
Developing Novel Therapies for GBM
Unfortunately, despite years of research, GBM remains incredibly difficult to treat and eradicate. There are a multitude of reasons for this. One aspect is the blood brain barrier, which is a tight network of cells around blood vessels in the brain, that is intended to protect the brain from foreign potentially harmful substances, In this instance, it often also prevents entry of drugs that may be potentially helpful. Therefore, it is important to find drugs and molecules that can permeate the blood brain barrier when developing therapies for GBM.
Another aspect as that GBM is a highly heterogeneous tumor. This means that there are multiple subpopulations within the tumor of different types of cells. There has been much work in the field to understand the different types of cells. From that work, three broad GBM subtypes have emerged that are helpful from a research perspective [5]. However, those subtypes have yet to show a clinical implication. Furthermore, there is additional heterogeneity even within the broad subtypes.
With all the different types of cells in GBM, it is difficult to find a single therapy that can eradicate every subpopulation evenly. Different cell have different sensitivities to therapy and therefore although some may be eradicated, others will still proliferate, therefore creating a recurrent tumor. In addition, with the different cells, there are also different capacities to adapt. One group of cells that has come out as being especially important and highly adaptable is cancer stem cells (CSCs). These likely play an important role in adapting to therapy through mutations and then repopulating the tumor. Together, these factors have made it difficult to find a drug or strategy that can truly eradicate the tumor (Figure 4).
Figure 4: Heterogeneity of GBM
Our Work
Our goals are to find better strategies for curing GBM by understanding genetic drivers of primary GBM, identifying mechanisms of resistance, and studying cancer stem cells. Learn more about our projects by clicking below!
In order to summarize existing literature for the scientific community, we have published (and continue to publish) a number of reviews on the above topics, as listed below.